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Archive for the ‘Calcium’ Category


Lesson 5 Cell Signaling And Motility: Cytoskeleton & Actin: Curations and Articles of reference as supplemental information: #TUBiol3373

Curator: Stephen J. Williams, Ph.D.

Cell motility or migration is an essential cellular process for a variety of biological events. In embryonic development, cells migrate to appropriate locations for the morphogenesis of tissues and organs. Cells need to migrate to heal the wound in repairing damaged tissue. Vascular endothelial cells (ECs) migrate to form new capillaries during angiogenesis. White blood cells migrate to the sites of inflammation to kill bacteria. Cancer cell metastasis involves their migration through the blood vessel wall to invade surrounding tissues.

Please Click on the Following Powerpoint Presentation for Lesson 4 on the Cytoskeleton, Actin, and Filaments

CLICK ON LINK BELOW

cell signaling 5 lesson

This post will be updated with further information when we get into Lesson 6 and complete our discussion on the Cytoskeleton

Please see the following articles on Actin and the Cytoskeleton in Cellular Signaling

Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

This article, constitutes a broad, but not complete review of the emerging discoveries of the critical role of calcium signaling on cell motility and, by extension, embryonic development, cancer metastasis, changes in vascular compliance at the junction between the endothelium and the underlying interstitial layer.  The effect of calcium signaling on the heart in arrhtmogenesis and heart failure will be a third in this series, while the binding of calcium to troponin C in the synchronous contraction of the myocardium had been discussed by Dr. Lev-Ari in Part I.

Universal MOTIFs essential to skeletal muscle, smooth muscle, cardiac syncytial muscle, endothelium, neovascularization, atherosclerosis and hypertension, cell division, embryogenesis, and cancer metastasis. The discussion will be presented in several parts:
1.  Biochemical and signaling cascades in cell motility
2.  Extracellular matrix and cell-ECM adhesions
3.  Actin dynamics in cell-cell adhesion
4.  Effect of intracellular Ca++ action on cell motility
5.  Regulation of the cytoskeleton
6.  Role of thymosin in actin-sequestration
7.  T-lymphocyte signaling and the actin cytoskeleton

 

Identification of Biomarkers that are Related to the Actin Cytoskeleton

In this article the Dr. Larry Bernstein covers two types of biomarker on the function of actin in cytoskeleton mobility in situ.

  • First, is an application in developing the actin or other component, for a biotarget and then, to be able to follow it as

(a) a biomarker either for diagnosis, or

(b) for the potential treatment prediction of disease free survival.

  • Second, is mostly in the context of MI, for which there is an abundance of work to reference, and a substantial body of knowledge about

(a) treatment and long term effects of diet, exercise, and

(b) underlying effects of therapeutic drugs.

Microtubule-Associated Protein Assembled on Polymerized Microtubules

(This article has a great 3D visualization of a microtuble structure as well as description of genetic diseases which result from mutations in tubulin and effects on intracellular trafficking of proteins.

A latticework of tiny tubes called microtubules gives your cells their shape and also acts like a railroad track that essential proteins travel on. But if there is a glitch in the connection between train and track, diseases can occur. In the November 24, 2015 issue of PNAS, Tatyana Polenova, Ph.D., Professor of Chemistry and Biochemistry, and her team at the University of Delaware (UD), together with John C. Williams, Ph.D., Associate Professor at the Beckman Research Institute of City of Hope in Duarte, California, reveal for the first time — atom by atom — the structure of a protein bound to a microtubule. The protein of focus, CAP-Gly, short for “cytoskeleton-associated protein-glycine-rich domains,” is a component of dynactin, which binds with the motor protein dynein to move cargoes of essential proteins along the microtubule tracks. Mutations in CAP-Gly have been linked to such neurological diseases and disorders as Perry syndrome and distal spinal bulbar muscular dystrophy.

 

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Lesson 4 Cell Signaling And Motility: G Proteins, Signal Transduction: Curations and Articles of reference as supplemental information: #TUBiol3373

Curator: Stephen J. Williams, Ph.D.

Updated 7/15/2019

Below please find the link to the Powerpoint presentation for lesson #4 for #TUBiol3373.  The lesson first competes the discussion on G Protein Coupled Receptors, including how cells terminate cell signals.  Included are mechanisms of receptor desensitization.  Please NOTE that desensitization mechanisms like B arrestin decoupling of G proteins and receptor endocytosis occur after REPEATED and HIGH exposures to agonist.  Hydrolysis of GTP of the alpha subunit of G proteins, removal of agonist, and the action of phosphodiesterase on the second messenger (cAMP or cGMP) is what results in the downslope of the effect curve, the termination of the signal after agonist-receptor interaction.

 

Click below for PowerPoint of lesson 4

Powerpoint for lesson 4

 

Please Click below for the papers for your Group presentations

paper 1: Membrane interactions of G proteins and other related proteins

paper 2: Macaluso_et_al-2002-Journal_of_Cellular_Physiology

paper 3: Interactions of Ras proteins with the plasma membrane

paper 4: Futosi_et_al-2016-Immunological_Reviews

 

Please find related article on G proteins and Receptor Tyrosine Kinases on this Open Access Online Journal

G Protein–Coupled Receptor and S-Nitrosylation in Cardiac Ischemia and Acute Coronary Syndrome

Action of Hormones on the Circulation

Newer Treatments for Depression: Monoamine, Neurotrophic Factor & Pharmacokinetic Hypotheses

VEGF activation and signaling, lysine methylation, and activation of receptor tyrosine kinase

 

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Lesson 9 Cell Signaling:  Curations and Articles of reference as supplemental information for lecture section on WNTs: #TUBiol3373

Stephen J. Wiilliams, Ph.D: Curator

UPDATED 4/23/2019

This has an updated lesson on WNT signaling.  Please click on the following and look at the slides labeled under lesson 10

cell motility 9b lesson_2018_sjw

Remember our lessons on the importance of signal termination.  The CANONICAL WNT signaling (that is the β-catenin dependent signaling)

is terminated by the APC-driven degradation complex.  This leads to the signal messenger  β-catenin being degraded by the proteosome.  Other examples of growth factor signaling that is terminated by a proteosome-directed include the Hedgehog signaling system, which is involved in growth and differentiation as well as WNTs and is implicated in various cancers.

A good article on the Hedgehog signaling pathway is found here:

The Voice of a Pathologist, Cancer Expert: Scientific Interpretation of Images: Cancer Signaling Pathways and Tumor Progression

All images in use for this article are under copyrights with Shutterstock.com

Cancer is expressed through a series of transformations equally involving metabolic enzymes and glucose, fat, and protein metabolism, and gene transcription, as a result of altered gene regulatory and transcription pathways, and also as a result of changes in cell-cell interactions.  These are embodied in the following series of graphics.

Figure 1: Sonic_hedgehog_pathwaySonic_hedgehog_pathway

The Voice of Dr. Larry

The figure shows a modification of nuclear translocation by Sonic hedgehog pathway. The hedgehog proteins have since been implicated in the development of internal organs, midline neurological structures, and the hematopoietic system in humans. The Hh signaling pathway consists of three main components: the receptor patched 1 (PTCH1), the seven transmembrane G-protein coupled receptor smoothened (SMO), and the intracellular glioma-associated oncogene homolog (GLI) family of transcription factors.5The GLI family is composed of three members, including GLI1 (gene activating), GLI2 (gene activating and repressive), and GLI3 (gene repressive).6 In the absence of an activating signal from either Shh, Ihh or Dhh, PTCH1 exerts an inhibitory effect on the signal transducer SMO, preventing any downstream signaling from occurring.7 When Hh ligands bind and activate PTCH1, the inhibition on SMO is released, allowing the translocation of SMO into the cytoplasm and its subsequent activation of the GLI family of transcription factors.

 

And from the review of  Elaine Y. C. HsiaYirui Gui, and Xiaoyan Zheng   Regulation of Hedgehog Signaling by Ubiquitination  Front Biol (Beijing). 2015 Jun; 10(3): 203–220.

the authors state:

Finally, termination of Hh signaling is also important for controlling the duration of pathway activity. Hh induced ubiquitination and degradation of Ci/Gli is the most well-established mechanism for limiting signal duration, and inhibiting this process can lead to cell patterning disruption and excessive cell proliferation (). In addition to Ci/Gli, a growing body of evidence suggests that ubiquitination also plays critical roles in regulating other Hh signaling components including Ptc, Smo, and Sufu. Thus, ubiquitination serves as a general mechanism in the dynamic regulation of the Hh pathway.

Overview of Hedgehog signaling showing the signal termination by ubiquitnation and subsequent degradation of the Gli transcriptional factors. obtained from Oncotarget 5(10):2881-911 · May 2014. GSK-3B as a Therapeutic Intervention in Cancer

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Note that in absence of Hedgehog ligands Ptch inhibits Smo accumulation and activation but upon binding of Hedgehog ligands (by an autocrine or paracrine fashion) Ptch is now unable to inhibit Smo (evidence exists that Ptch is now targeted for degradation) and Smo can now inhibit Sufu-dependent and GSK-3B dependent induced degradation of Gli factors Gli1 and Gli2.  Also note the Gli1 and Gli2 are transcriptional activators while Gli3 is a transcriptional repressor.

UPDATED 4/16/2019

Please click on the following links for the Powerpoint presentation for lesson 9.  In addition click on the mp4 links to download the movies so you can view them in Powerpoint slide 22:

cell motility 9 lesson_SJW 2019

movie file 1:

Tumorigenic but noninvasive MCF-7 cells motility on an extracellular matrix derived from normal (3DCntrol) or tumor associated (TA) fibroblasts.  Note that TA ECM is “soft” and not organized and tumor cells appear to move randomly if  much at all.

Movie 2:

 

Note that these tumorigenic and invasive MDA-MB-231 breast cancer cells move in organized patterns on organized ECM derived from Tumor Associated (TA) fibroblasts than from the ‘soft’ or unorganized ECM derived from normal  (3DCntrl) fibroblasts

 

The following contain curations of scientific articles from the site https://pharmaceuticalintelligence.com  intended as additional reference material  to supplement material presented in the lecture.

Wnts are a family of lipid-modified secreted glycoproteins which are involved in:

Normal physiological processes including

A. Development:

– Osteogenesis and adipogenesis (Loss of wnt/β‐catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes)

  – embryogenesis including body axis patterning, cell fate specification, cell proliferation and cell migration

B. tissue regeneration in adult tissue

read: Wnt signaling in the intestinal epithelium: from endoderm to cancer

And in pathologic processes such as oncogenesis (refer to Wnt/β-catenin Signaling [7.10]) and to your Powerpoint presentation

 

The curation Wnt/β-catenin Signaling is a comprehensive review of canonical and noncanonical Wnt signaling pathways

 

To review:

 

 

 

 

 

 

 

 

 

 

 

Activating the canonical Wnt pathway frees B-catenin from the degradation complex, resulting in B-catenin translocating to the nucleus and resultant transcription of B-catenin/TCF/LEF target genes.

Fig. 1 Canonical Wnt/FZD signaling pathway. (A) In the absence of Wnt signaling, soluble β-catenin is phosphorylated by a degradation complex consisting of the kinases GSK3β and CK1α and the scaffolding proteins APC and Axin1. Phosphorylated β-catenin is targeted for proteasomal degradation after ubiquitination by the SCF protein complex. In the nucleus and in the absence of β-catenin, TCF/LEF transcription factor activity is repressed by TLE-1; (B) activation of the canonical Wnt/FZD signaling leads to phosphorylation of Dvl/Dsh, which in turn recruits Axin1 and GSK3β adjacent to the plasma membrane, thus preventing the formation of the degradation complex. As a result, β-catenin accumulates in the cytoplasm and translocates into the nucleus, where it promotes the expression of target genes via interaction with TCF/LEF transcription factors and other proteins such as CBP, Bcl9, and Pygo.

NOTE: In the canonical signaling, the Wnt signal is transmitted via the Frizzled/LRP5/6 activated receptor to INACTIVATE the degradation complex thus allowing free B-catenin to act as the ultimate transducer of the signal.

Remember, as we discussed, the most frequent cancer-related mutations of WNT pathway constituents is in APC.

This shows how important the degradation complex is in controlling canonical WNT signaling.

Other cell signaling systems are controlled by protein degradation:

A.  The Forkhead family of transcription factors

Read: Regulation of FoxO protein stability via ubiquitination and proteasome degradation

B. Tumor necrosis factor α/NF κB signaling

Read: NF-κB, the first quarter-century: remarkable progress and outstanding questions

1.            Question: In cell involving G-proteins, the signal can be terminated by desensitization mechanisms.  How is both the canonical and noncanonical Wnt signal eventually terminated/desensitized?

We also discussed the noncanonical Wnt signaling pathway (independent of B-catenin induced transcriptional activity).  Note that the canonical and noncanonical involve different transducers of the signal.

Noncanonical WNT Signaling

Note: In noncanonical signaling the transducer is a G-protein and second messenger system is IP3/DAG/Ca++ and/or kinases such as MAPK, JNK.

Depending on the different combinations of WNT ligands and the receptors, WNT signaling activates several different intracellular pathways  (i.e. canonical versus noncanonical)

 

In addition different Wnt ligands are expressed at different times (temporally) and different cell types in development and in the process of oncogenesis. 

The following paper on Wnt signaling in ovarian oncogenesis shows how certain Wnt ligands are expressed in normal epithelial cells but the Wnt expression pattern changes upon transformation and ovarian oncogenesis. In addition, differential expression of canonical versus noncanonical WNT ligands occur during the process of oncogenesis (for example below the authors describe the noncanonical WNT5a is expressed in normal ovarian  epithelia yet WNT5a expression in ovarian cancer is lower than the underlying normal epithelium. However the canonical WNT10a, overexpressed in ovarian cancer cells, serves as an oncogene, promoting oncogenesis and tumor growth.

Wnt5a Suppresses Epithelial Ovarian Cancer by Promoting Cellular Senescence

Benjamin G. Bitler,1 Jasmine P. Nicodemus,1 Hua Li,1 Qi Cai,2 Hong Wu,3 Xiang Hua,4 Tianyu Li,5 Michael J. Birrer,6Andrew K. Godwin,7 Paul Cairns,8 and Rugang Zhang1,*

A.           Abstract

Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy in the US. Thus, there is an urgent need to develop novel therapeutics for this disease. Cellular senescence is an important tumor suppression mechanism that has recently been suggested as a novel mechanism to target for developing cancer therapeutics. Wnt5a is a non-canonical Wnt ligand that plays a context-dependent role in human cancers. Here, we investigate the role of Wnt5a in regulating senescence of EOC cells. We demonstrate that Wnt5a is expressed at significantly lower levels in human EOC cell lines and in primary human EOCs (n = 130) compared with either normal ovarian surface epithelium (n = 31; p = 0.039) or fallopian tube epithelium (n = 28; p < 0.001). Notably, a lower level of Wnt5a expression correlates with tumor stage (p = 0.003) and predicts shorter overall survival in EOC patients (p = 0.003). Significantly, restoration of Wnt5a expression inhibits the proliferation of human EOC cells both in vitro and in vivo in an orthotopic EOC mouse model. Mechanistically, Wnt5a antagonizes canonical Wnt/β-catenin signaling and induces cellular senescence by activating the histone repressor A (HIRA)/promyelocytic leukemia (PML) senescence pathway. In summary, we show that loss of Wnt5a predicts poor outcome in EOC patients and Wnt5a suppresses the growth of EOC cells by triggering cellular senescence. We suggest that strategies to drive senescence in EOC cells by reconstituting Wnt5a signaling may offer an effective new strategy for EOC therapy.

Oncol Lett. 2017 Dec;14(6):6611-6617. doi: 10.3892/ol.2017.7062. Epub 2017 Sep 26.

Clinical significance and biological role of Wnt10a in ovarian cancer. 

Li P1Liu W1Xu Q1Wang C1.

Ovarian cancer is one of the five most malignant types of cancer in females, and the only currently effective therapy is surgical resection combined with chemotherapy. Wnt family member 10A (Wnt10a) has previously been identified to serve an oncogenic function in several tumor types, and was revealed to have clinical significance in renal cell carcinoma; however, there is still only limited information regarding the function of Wnt10a in the carcinogenesis of ovarian cancer. The present study identified increased expression levels of Wnt10a in two cell lines, SKOV3 and A2780, using reverse transcription-polymerase chain reaction. Functional analysis indicated that the viability rate and migratory ability of SKOV3 cells was significantly inhibited following Wnt10a knockdown using short interfering RNA (siRNA) technology. The viability rate of SKOV3 cells decreased by ~60% compared with the control and the migratory ability was only ~30% of that in the control. Furthermore, the expression levels of β-catenin, transcription factor 4, lymphoid enhancer binding factor 1 and cyclin D1 were significantly downregulated in SKOV3 cells treated with Wnt10a-siRNA3 or LGK-974, a specific inhibitor of the canonical Wnt signaling pathway. However, there were no synergistic effects observed between Wnt10a siRNA3 and LGK-974, which indicated that Wnt10a activated the Wnt/β-catenin signaling pathway in SKOV3 cells. In addition, using quantitative PCR, Wnt10a was overexpressed in the tumor tissue samples obtained from 86 patients with ovarian cancer when compared with matching paratumoral tissues. Clinicopathological association analysis revealed that Wnt10a was significantly associated with high-grade (grade III, P=0.031) and late-stage (T4, P=0.008) ovarian cancer. Furthermore, the estimated 5-year survival rate was 18.4% for patients with low Wnt10a expression levels (n=38), whereas for patients with high Wnt10a expression (n=48) the rate was 6.3%. The results of the present study suggested that Wnt10a serves an oncogenic role during the carcinogenesis and progression of ovarian cancer via the Wnt/β-catenin signaling pathway.

Targeting the Wnt Pathway includes curations of articles related to the clinical development of Wnt signaling inhibitors as a therapeutic target in various cancers including hepatocellular carcinoma, colon, breast and potentially ovarian cancer.

 

2.         Question: Given that different Wnt ligands and receptors activate different signaling pathways, AND  WNT ligands  can be deferentially and temporally expressed  in various tumor types and the process of oncogenesis, how would you approach a personalized therapy targeting the WNT signaling pathway?

3.         Question: What are the potential mechanisms of either intrinsic or acquired resistance to Wnt ligand antagonists being developed?

 

Other related articles published in this Open Access Online Scientific Journal include the following:

Targeting the Wnt Pathway [7.11]

Wnt/β-catenin Signaling [7.10]

Cancer Signaling Pathways and Tumor Progression: Images of Biological Processes in the Voice of a Pathologist Cancer Expert

e-Scientific Publishing: The Competitive Advantage of a Powerhouse for Curation of Scientific Findings and Methodology Development for e-Scientific Publishing – LPBI Group, A Case in Point 

Electronic Scientific AGORA: Comment Exchanges by Global Scientists on Articles published in the Open Access Journal @pharmaceuticalintelligence.com – Four Case Studies

 

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“Minerals in Medicine” –  40 Minerals that are crucial to Human Health and Biomedicine: Exhibit by NIH Clinical Center and The Smithsonian Institution National Museum of Natural History

Reporter: Aviva Lev-Ari, PhD, RN

 

Friday, September 9, 2016

NIH Clinical Center and The Smithsonian Institution partner to launch Minerals in Medicine Exhibition

What

The National Institutes of Health Clinical Center, in partnership with The Smithsonian Institution National Museum of Natural History, will open a special exhibition of more than 40 minerals that are crucial to human health and biomedicine. “Minerals in Medicine” is designed to enthrall and enlighten NIH Clinical Center’s patients, their loved ones, and the NIH community. Media are invited into America’s Research Hospital, the NIH Clinical Center, to experience this unique exhibition during a ribbon cutting ceremony on Monday September 12 at 4pm.

Beyond taking in the minerals’ arresting beauty, spectators can learn about their important role in keeping the human body healthy, and in enabling the creation of life-saving medicines and cutting edge medical equipment that is used in the NIH Clinical Center and healthcare facilities worldwide. The exhibition, which is on an eighteen-month loan from the National Museum of Natural History, includes specimens that were handpicked from the museum’s vast collection by NIH physicians in partnership with Smithsonian Institution geologists. Some of the minerals on display were obtained regionally as they are part of the Maryland and Virginia landscape.

Who

  • John I. Gallin, M.D., Director of the NIH Clinical Center
  • Jeffrey E. Post, Ph.D., Smithsonian Institution National Museum of Natural History, Chair of the Department of Mineral Sciences and Curator of the National Gem and Mineral Collection

When

Monday, September 12, 2016, 4:00 – 5:00 p.m.

Where

NIH Clinical Center (Building 10), 10 Center Drive, Bethesda, MD, 20892; 1st Floor near Admissions

How

RSVP encouraged, but not required, to attend in person. NIH Visitors Map: http://www.ors.od.nih.gov/maps/Pages/NIH-Visitor-Map.aspx

About the NIH Clinical Center: The NIH Clinical Center is the clinical research hospital for the National Institutes of Health. Through clinical research, clinician-investigators translate laboratory discoveries into better treatments, therapies and interventions to improve the nation’s health. More information: http://clinicalcenter.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

SOURCE

https://www.nih.gov/news-events/news-releases/nih-clinical-center-smithsonian-institution-partner-launch-minerals-medicine-exhibition

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Bisphosphonates and Bone Metastasis [6.3.1]

Curator: Stephen J. Williams, Ph.D.

bisophosphonates chemical

General Structure of Bisphosphonates

One of the hallmarks of advanced cancer is the ability to metastasize (tumor cells migrating from primary tumor and colonize in a different anatomical site in the body) and many histologic types of primary tumors have the propensity to metastasize to the bone. One of the frequent complications occurring from bone metastasis is bone fractures and severe pain associated with these cancer-associated bone fractures. An additional problem is cancer-associated hypercalcemia, which may or may not be dependent on bone-metastasis. The main humoral factor associated with cancer-related hypercalcemia is parathyroid hormone–related protein, which is produced by many solid tumors (Paget’s disease). Parathyroid hormone–related protein increases calcium by activating parathyroid hormone receptors in tissue, which results in osteoclastic bone resorption; it also increases renal tubular resorption of calcium {see (1) Bower reference for more information). This curation involves three areas:

  1. The Changing Views How Bone Remodeling Occurs
  2. Early Development of Agents that Alter Bone Remodeling and Early Use in Cancer Patients
  3. Recent Developments Regarding Use of Bisphosphonates in Cancer Patients

As there are numerous articles (1360; more than to manually curate) on “bone”, “metastasis” and “bisphosphonates” the following link is to a Pubmed search on the terms

http://www.ncbi.nlm.nih.gov/pubmed/?term=bone+metastasis+bisphosphonates

In addition there are subset searches to show use of bisphosphonates in common cancers and files given below with numbers of articles:

Search terms with Pubmed link # citations
bone metastasis bisphosphonates 1360
+ breast 559
+ prostate 349
+ colon 9
+ lung 222
  1. The Changing Views How Bone Remodeling Occurs

Bone remodeling (or bone metabolism) is a lifelong process where mature bone tissue is removed from the skeleton (a process called bone resorption) and new bone tissue is formed (a process called ossification or new bone formation). These processes also control the reshaping or replacement of bone following injuries like fractures but also micro-damage, which occurs during normal activity. Remodeling responds also to functional demands of the mechanical loading.

In the first year of life, almost 100% of the skeleton is replaced. In adults, remodeling proceeds at about 10% per year.[1]

An imbalance in the regulation of bone remodeling’s two sub-processes, bone resorption and bone formation, results in many metabolic bone diseases, such as osteoporosis. Two main types of cells are responsible for bone metabolism: osteoblasts (which secrete new bone), and osteoclasts (which break bone down). The structure of bones as well as adequate supply of calcium requires close cooperation between these two cell types and other cell populations present at the bone remodeling sites (ex. immune cells).[4] Bone metabolism relies on complex signaling pathways and control mechanisms to achieve proper rates of growth and differentiation. These controls include the action of several hormones, including parathyroid hormone (PTH), vitamin D, growth hormone, steroids, and calcitonin, as well as several bone marrow-derived membrane and soluble cytokines and growth factors (ex. M-CSF, RANKL, VEGF, IL-6 family…). It is in this way that the body is able to maintain proper levels of calcium required for physiological processes.

Subsequent to appropriate signaling, osteoclasts move to resorb the surface of the bone, followed by deposition of bone by osteoblasts. Together, the cells that are responsible for bone remodeling are known as the basic multicellular unit (BMU), and the temporal duration (i.e. lifespan) of the BMU is referred to as the bone remodeling period.

For a good review on bone remodeling please see Bone remodelling in a nutshell

boneremodelPTHumich

bone remodeling 3

  1. Early Development of Agents that Alter Bone Remodeling and Early Use in Cancer Patients

Bisphosphonates had been first synthesized in the late 1800’s yet their development and approval for the indication of osteoporosis occurred over 100 years later, in the 1990’s. For a good review on the history of bisphosphonates please see the following review:

Historical perspectives on the clinical development of bisphosphonates in the treatment of bone diseases. Francis MD1, Valent DJ. J Musculoskelet Neuronal Interact. 2007 Jan-Mar;7(1):2-8.

For a good reference on bisphosphonates as a class, as well as indication, contraindication and side effects see University of Washington web page at http://courses.washington.edu/bonephys/opbis.html

 

Please view slideshow in the following link: The Evolving Role of Bisphosphonates for Cancer Treatment-Induced Bone Loss presentation by Richard L. Theriault, DO, MBA at MD Anderson Cancer Center

bisphosphonatecancerslide1

  1. Recent Developments Regarding Use of Bisphosphonates in Cancer Patients

Bone Metastasis Treatment with Bisphosphonates; A review form OncoLink

Source: From University of Pennsylvania OncoLink® at http://www.oncolink.org/types/article.cfm?c=708&id=9629

Julia Draznin Maltzman, MD and Modified by Lara Bonner Millar, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 18, 2014

Introduction

Bone metastases are a common complication of advanced cancer. They are especially prevalent (up to 70%) in breast and prostate cancer. Bone metastases can cause severe pain, bone fractures, life-threatening electrolyte imbalances, and nerve compression syndromes. The pain and neurologic dysfunction may be difficult to treat and significantly compromises the patients’ quality of life. Bone metastases usually signify advanced, often incurable disease.

Osteolytic vs. osteoblastic

Bony metastases are characterized as being either osteolytic or osteoblastic. Osteolytic means that the tumor caused bone break down or dissolution. This usually results in loss of calcium from bone. On X-rays these are seen as holes called “lucencies” within the bone. Diffuse osteolytic lesions are most characteristic of a blood cancer called Multiple Myeloma, however they may be present in patients with many other types of cancer.

Osteoblastic bony lesions, by contrast, are characterized by increased bone production. The tumor somehow signals to the bone to overproduce bone cells and result in rigid, inflexible bone formation. The cancer that typically causes osteoblastic bony lesions is prostate cancer. Most cancers result in either osteolytic or osteoblastic bony changes, but some malignancies can lead to both. Breast cancer patients usually develop osteolytic lesions, although at least 15-20 percent can have osteoblastic pathology.

Why the bone?

The bone is a common site of metastasis for many solid tissue cancers including prostate, breast, lung, kidney, stomach, bladder, uterus, thyroid, colon and rectum. Researchers speculate that this may be due to the high blood flow to the bone and bone marrow. Once cancer cells gain access to the blood vessels, they can travel all over the body and usually go where there is the highest flow of blood. Furthermore, tumor cells themselves secrete adhesive molecules that can bind to the bone marrow and bone matrix. This molecular interaction can cause the tumor to signal for increased bone destruction and enhance tumor growth within the bone. A recent scientific discovery showed that the bone is actually a rich source of growth factors. These growth factors signal cells to divide, grow, and mature. As the cancer attacks the bone, these growth factors are released and serve to further stimulate the tumor cells to grow. This results in a self-generating growth loop.

What are the symptoms of bone metastasis?

It must be recognized that the symptoms of bone metastasis can mimic many other disease conditions. Most people with bony pain do not have bone metastasis. That being noted, the most common symptom of a metastasis to the bone is pain. Another common presentation is a bone fracture without any history of trauma. Fracture is more common in lytic metastases than blastic metastases.

Some people with more advanced disease may come to medical attention because of numbness and tingling sensation in their feet and legs. They may have bowel and bladder dysfunction – either losing continence to urine and/or stool, or severe constipation and urinary retention. Others may complain of leg weakness and difficulty moving their legs against gravity. This would imply that there is tumor impinging on the spinal cord and compromising the nerves. This is considered an emergency called spinal cord compression, and requires immediate medical attention. Another less common presentation of metastatic disease to the bone is high levels of calcium in the body. High calcium can make patients constipated, result in abdominal pain, and at very high levels, can lead to confusion and mental status changes.

Diagnosis of bone metastasis

Once a patient experiences any of the symptoms of bone metastasis, various tests can be done to find the true cause. In some cases bone metastasis can be detected before the symptoms arise. X-rays, bone scans, and MRIs are used to diagnose this complication of cancer. X-rays are especially helpful in finding osteolytic lesions. These often appear as “holes” or dark spots in the bone on the x-ray film. Unfortunately, bone metastases often do not show up on plain x-rays until they are quite advanced. By contrast, a bone scan can detect very early bone metastases. This test is done by injecting the patient with a small amount of radio-tracing material in the vein. Special x-rays are taken sometime after the injection. The radiotracer will preferentially go to the site of disease and will appear as a darker, denser, area on the film. Because this technique is so sensitive, sometimes infections, arthritis, and old fractures can appear as dark spots on the bone scan and may be difficult to differentiate from a true cancer. Bone scans are also used to follow patients with known bone metastasis. Sometimes CT scan images can show if a cancer has spread to the bone. An MRI is most useful when examining nerve roots suspected of being compressed by tumor or bone fragments due to tumor destruction. It is used most often in the setting of spinal cord compromise.

There are no real blood tests that are currently used to diagnose a bone metastasis. There are, however, a number of blood tests that a provider can obtain that may suggest the presence of bone lesions, but the diagnosis rests with the combination of radiographic evidence, clinical picture, and natural history of the malignancy. For example, elevated levels of calcium or an enzyme called alkaline phosphatase can be related to bone metastasis, but these lab tests alone are insufficient to prove their presence.

Treatment

The best treatment for bony metastasis is the treatment of the primary cancer. Therapies may include chemotherapy, hormone therapy, radiation therapy, immunotherapy, or treatment with monoclonal antibodies. Pain is often treated with narcotics and other pain medications, such as non-steroidal anti-inflammatory agents. Physical therapy may be helpful and surgery may have an important role if the cancer resulted in a fracture of the bone.

Bisphosphonates

Bisphosphonates are s category of medications that decrease pain from bone metastasis and may improve overall bone health. Bisphosphonates man-made versions of a naturally occurring compound called pyrophosphate that prevents bone breakdown. They are a class of medications widely used in the treatment and prevention of osteoporosis and certain other bone diseases (such as Paget’s Disease), as well as in the treatment of elevated blood calcium. These drugs suppress bone breakdown by cells called osteoclasts, and, can indirectly stimulate the bone forming cells called osteoblasts. It is for this reason, and for the fact that bisphosphonates are very effective in relieving bone pain associated with metastatic disease, that they have transitioned to the oncology arena. However, treatment of bone metastases is not curative. There is increasing evidence that bisphosphonates can prevent bony complications in some metastatic cancers and may even improve survival in some cancers. Most researchers agree that these drugs are more helpful in osteolytic lesions and less so in osteoblastic metastasis in terms of bone restoration and health, but the bisphosphonates are able to alleviate pain associated with both types of lesions. The appropriate time to start treatment is once a bone metastasis has been identified on imaging.

Bisphosphonates can be given either orally or intravenously. The latter is the preferred route of administration for many oncologists as it is given monthly as a short infusion and does not have the gastrointestinal side effects that the oral bisphosphonates have. There are currently two approved and commonly used IV bisphosphonates –Pamidronate disodium (Aredia, Novartis) and zolendronic acid (Zometa, Novartis). Their side effect profile is fairly mild and includes a flu-like reaction during the first 48 hours after the infusion, kidney impairment and osteonecrosis of the jaw with long term use. Patients with renal impairment may not be candidates for this therapy.

Bisphophonates may have some level of anti-tumor activity in breast cancer. A recent Phase III clinical trial revealed that the addition of Zometa to endocrine therapy, improves disease-free survival, but not overall survival, in pre-menopausal patients with estrogen-receptor postive early breast cancer. Another trial called AZURE found no effect from the bisphosphonate zolendronic acid (Zometa, Novartis) on the recurrence of breast cancer or on overall survival. However, several other studies on bisphosphonates and breast cancer are ongoing, and for now, their use is not recommended in patients without metastases.

In addition to bisphosphonates, osteoclast inhibition can also be achieved through other means. Another medication, Denosumab (XGEVA, Amgen), targets a receptor called receptor activator of nuclear factor kappa B ligand (RANKL), is able to block osteoclast formation. A few studies comparing Denosumab to bisphosphonates have found Denosumab results in a longer time to skeletal events, on the order of a few months, compared to bisphosphonates, however many experts believe that the evidence is not strong enough to support one class of drug over another. The most common side effects of Denosumab are fatigue or asthenia, hypophosphatemia, hypocalcemia and nausea. Patients receiving bisphosphonates or denosumab should also be taking calcium and vitamin D supplementation.

The future

Skeletal metastases remain one of the more debilitating problems for cancer patients. Research is ongoing to identify the molecular mechanisms that result in both osteolytic and osteoblastic bone lesions. Perhaps the use of proteomics and gene array data may permit us to identify some factors specific to the tumor or to the bony lesion itself that could be used as therapeutic targets to teat or even prevent this complication.

In summary

  •  there is well established evidence in preclinical models that bisphosphonates:reduce the total tumor burden in bone
  • it is unclear as to the mechanisms of this preclinical finding as bisphosphonates have been shown to directly have antitumor activity
  • as the review by Holen I1, Coleman RE.show “Bisphosphonates as treatment of bone metastases” (abstract given below) there is conflicting clinical evidence of this effect found in preclinical models

Accelerated bone loss is a common clinical feature of advanced breast cancer, and anti-resorptive bisphosphonates are the current standard therapy used to reduce the number and frequency of skeletal-related complications experienced by patients. Bisphosphonates are potent inhibitors of bone resorption, acting by inducing osteoclast apoptosis and thereby preventing the development of cancer-induced bone lesions. In clinical use bisphosphonates are mainly considered to be bone-specific agents, but anti-tumour effects have been reported in a number of in vitro and in vivo studies. By combining bisphosphonates with chemotherapy agents, growth and progression of breast cancer bone metastases can be virtually eliminated in model systems. Recent clinical trials have indicated that there may be additional benefits from bisphosphonate treatment, including positive effects on recurrence and survival when added to standard endocrine therapy. Whereas the ability of bisphosphonates to reduce cancer-induced bone disease is well established, their potential direct anti-tumour effect remain controversial. Ongoing clinical trials will establish whether bisphosphonates can inhibit the development of bone metastases in high-risk breast cancer patients. This review summarizes the main studies that have investigated the effects of bisphosphonates, alone and in combination with other anti-cancer agents, using in vivo model systems of breast cancer bone metastases. We also give an overview of the use of bisphosphonates in the treatment of breast cancer, including examples of key clinical trials. The potential side effects and future clinical applications of bisphosphonates will be outlined.

References

  1. Bower M, Cox S. Endocrine and metabolic complications of advanced cancer. In: Doyle D, Hanks G, Cherny NI, Calman K, editors. Oxford textbook of palliative medicine. 3rd ed. New York, NY: Oxford University Press; 2004. p. 688-90.

Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29(9):1125-32.

Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol. 2011;29(9):1221-7.

West, H. Denosumab for prevention of skeletal-related events in patients with bone metastases from solid tumors: incremental benefit, debatable value. J Clin Oncol. 2011;29(9):1095-8.

Gnant M, Mlineritsch B, Schippinger W et al.: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 360(7),679–691 (2009).

Treatment Guidelines by Cancer Organizations

ASCO Issues Updated Guideline on the Role of Bone-Modifying Agents in the Prevention and Treatment of Bone Metastases in Patients with Metastatic Breast Cancer

For Immediate Release

February 22, 2011

Contact:

Steven Benowitz
571-483-1370
steven.benowitz@asco.org

ALEXANDRIA, Va. – The American Society of Clinical Oncology (ASCO) today issued an update to its clinical practice guideline on the use of bone-modifying agents, in particular, osteoclast inhibitors, to prevent and treat skeletal complications from bone metastases in patients with metastatic breast cancer. The new guideline includes recommendations on the use of a new drug option, denosumab (Xgeva), and addresses osteonecrosis of the jaw, an uncommon condition that may occur in association with bone-modifying agents. The updated guideline also provides new recommendations on monitoring of patients who undergo treatment with bone-modifying agents and highlights priorities for future research on these drugs.

ASCO’s Bisphosphonates in Breast Cancer Panel conducted a systematic review of the medical literature to develop the new recommendations. The updated guideline, American Society of Clinical Oncology Clinical Practice Guideline Update on the Role of Bone-Modifying Agents in Metastatic Breast Cancer, was published online today in the Journal of Clinical Oncology.

The guideline recommends that patients with breast cancer who have evidence of bone metastases be given one of three agents – denosumab, pamidronate or zoledronic acid – approved by the U.S. Food and Drug Administration. It does not support use of any one drug over the others. These drugs are all considered osteoclast inhibitors, but they belong to different drug families: pamidronate and zoledronic acid are part of a class of drugs called bisphosphonates, while denosumab is a monoclonal antibody that targets receptor activator of nuclear factor-kappa beta ligand (RANKL).

The guideline also recommends against initiating bone-modifying agents in the absence of bone metastases outside of a clinical trial. It notes that an abnormal bone scan result alone, without confirmation by a radiograph, CT or MRI scan, is not sufficient evidence to support treatment with these drugs.

“The updated recommendations take into account recent progress in controlling potential bone damage in metastatic breast cancer,” said Catherine Van Poznak, MD, co-chair of the Bisphosphonates in Breast Cancer Panel and assistant professor of medicine at the University of Michigan. “We’ve established that a growing number of osteoclast inhibitors can have a positive effect and decrease of the risk of skeletal-related events in women with bone metastases. Because many factors – including medical and economic – must be considered when selecting a therapy for an individual, it’s good to have several effective choices.”

Bone is one of the most common sites to which breast cancer spreads. Bone metastases occur in approximately 70 percent of patients with metastatic disease. These metastases can cause bone cells (osteoclasts) to become overactive, which can result in excessive bone loss, disrupting the bone architecture and causing skeletal-related events (SREs), such as fracture, the need for surgery or radiation therapy to bone, spinal cord compression and hypercalcemia of malignancy.

This document updates guideline recommendations that were first issued in 2000 and revised in 2003, and focused on the use of bisphosphonates. The current guideline uses the more inclusive term, bone-modifying agents, to reflect a wider category of therapeutic agents such as monoclonal antibodies that use different mechanisms of action to prevent and treat damage from bone metastases. The guideline notes that research remains to be conducted to address several areas where questions remain.

“The guideline considers new data in a variety of areas, including studies showing that denosumab has equivalent effectiveness compared with other currently available drug therapies,” explained bisphosphonates panel co-chair Jamie Von Roenn, MD, professor of medicine at Northwestern University. “The guideline also provides guidance on preventing a rare, but significant complication of therapy with bone-modifying agents, osteonecrosis of the jaw.”

Denosumab is a human monoclonal antibody that targets a receptor, RANKL, involved in the regulation of bone remodeling. The guideline cites evidence from a randomized Phase III trial showing that denosumab appears to be comparable to zoledronic acid in reducing the risk of SREs in women with bone metastases from breast cancer. Denosumab is given subcutaneously, and can have side effects such as hypocalcemia.

The guideline also addresses the recently discovered osteonecrosis of the jaw. The first reports of this degenerative condition were published in the medical and dental literature in 2003. The committee recommended that all patients with breast cancer get dental evaluations and receive preventive dentistry care before beginning treatment with bone-modifying osteoclast inhibitors.

The panel updated its recommendations regarding the effects of bisphosphonates on kidney function, particularly for those taking either pamidronate or zoledronic acid, which have been associated with deteriorating kidney function. It said that clinicians should monitor serum creatinine clearance prior to each dose of pamidronate or zoledronic acid according to FDA-approved labeling.

The panel did not recommend using biochemical markers to monitor bone-modifying agent effectiveness and use outside of a clinical trial.

While many of the 2003 recommendations remain the same, the guideline notes several research directions to be addressed, including:

  • Duration of therapy with bone modifying agents, and the timing or intervals between delivery.
  • The development of a risk index for SREs, and better ways to stratify patient risk of SRE or risk of toxicity from a bone-modifying agent. Individual risk may guide selection of timing for use of a bone-modifying agent therapy.
  • Trials specifically examining whether stage IV breast cancer patients who do not have evidence of bone metastases would benefit from bone-modifying agents.
  • The role of biomarkers in treatment selection and monitoring drug effectiveness.
  • Understanding the optimal dosing of calcium and vitamin D supplementation in patients treated with bone-modifying agents.

The meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) was published in Lancet and suggested that “Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began”.

Results

  • Of 18, 206 women in trials of 2-5 years of bisphosphonate3453 first recurrences, and 2106 subsequent deaths.
  • Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance
  • Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). “This was iregardless of age or bisphosphonate type.

Lancet. 2015 Jul 23. pii: S0140-6736(15)60908-4. doi: 10.1016/S0140-6736(15)60908-4. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials.

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).

This Study was reported at the 36th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S4-07. Presented December 12, 2013 and Medscape Medical News journalist Kate Johnson covered the finding with author interviews in the following article:

Bisphosphonates: ‘New Addition’ to Breast Cancer Treatment?

Kate Johnson

December 13, 2013

Editors’ Recommendations

SAN ANTONIO — Adjuvant bisphosphonate treatment significantly improves breast cancer survival and reduces bone recurrence in postmenopausal women with early breast cancer, according to a meta-analysis reported here at the 36th Annual San Antonio Breast Cancer Symposium.

“We have finally defined a new addition to standard treatment,” announced lead investigator Robert Coleman, MD, professor of oncology at the University of Sheffield in the United Kingdom. He emphasized that, as hypothesized, the benefits of this therapy were confined to postmenopausal women.

“There is absolutely no effect on mortality in premenopausal women, with a hazard ratio [HR] of 1.0,” he reported. “But for postmenopausal women, we see a 17% reduction in the risk of death [HR, 0.83], which is highly statistically significant.”

In terms of the absolute benefit, bisphosphonates decreased the breast cancer mortality rate from 18.3% to 15.2% in postmenopausal women (P = .004).

The separation of benefit by menopausal status was also seen in the bone recurrence data.

In premenopausal women, there is no significant effect on bone recurrence (HR, 0.93), whereas in postmenopausal women, there was a 34% reduction. The difference was “highly significant,” said Dr. Coleman.

“I personally believe adjuvant bisphosphonates should be standard treatment in postmenopausal women with breast cancer,” said Michael Gnant, MD, professor of surgery at the Medical University of Vienna, who was one of the study investigators. He spoke during a plenary session before the results were formally announced. (Please click this LINK to See VIDEO Interview with Dr. Gnant)

“This is an important analysis,” said Rowan Chlebowski, MD, PhD, medical oncologist from the Harbor-UCLA Medical Center in Los Angeles.

“There will be a substantial increase in the use of bisphosphonates,” he told Medscape Medical News after the presentation.

“The only question is whether people will accept this analysis as the final word.” Dr. Chlebowski explained that some people might criticize the study as being a post hoc analysis of previous findings.

“You might find some mixed feelings about whether this should be accepted, but I think this will get people thinking,” he said. Dr. Chlebowski previously reported a large observational study that demonstrated that postmenopausal women taking oral bisphosphonates for osteoporosis had a significantly lower risk for breast cancer.

Bisphosphonates were originally indicated for the treatment of osteoporosis, and include agents such as alendronate (Fosamax, Merck), ibandronate (Boniva, Genentech), risedronate (Actonel, sanofi-aventis), and zoledronic acid (Reclast, Novartis). But they are also indicated for bone-related use in breast cancer patients, Dr. Chlebowski pointed out.

Because bisphosphonates “also have an indication for preventing bone loss associated with aromatase inhibitor use, they are already approved in this setting, and would prevent recurrences. It will be interesting to see if guideline panels” like these findings, he noted.

Why Postmenopausal Women Benefit

In the plenary session, Dr. Gnant acknowledged that the data on bisphosphonates to date have been mixed.

There are “many trials showing controversial results” for bisphosphonates in the context of breast cancer, he said. “When we put them all together in an unselected population, some show beneficial effects and some do not.”

Dr. Gnant explained why bisphosphonates appear to be effective in older but not younger women. “When you confine your analysis to the low-estrogen environment, postmenopausal women, or women rendered menopausal by ovarian function suppression, we see that all these trials show a consistent benefit for these patients,” he said.

“Essentially, this low-estrogen hypothesis as a prerequisite for adjuvant bisphosphonate activity means that we believe these treatments can silence the bone marrow microenvironment. However, this only translates to relevant clinical benefits in low-estrogen environments,” he added.

More Study Details

The meta-analysis involved 36 trials of adjuvant bisphosphonates in breast cancer with 17,791 pre- and postmenopausal women.

The primary outcomes of the study were time to distant recurrence, local recurrence, and new second primary breast cancer (ipsilateral or contralateral), time to first distant recurrence (ignoring any previous locoregional or contralateral recurrences), and breast cancer mortality.

Planned subgroup analyses based on hypotheses generated from previous findings included site of recurrence, site of first distant metastasis, menopausal status, and type and schedule of bisphosphonate therapy, said Dr. Coleman.

With bisphosphonate therapy, there was a nonsignificant 1% reduction in breast cancer recurrence at 10 years in postmenopausal women, compared with premenopausal women (25.4% vs 26.5%), and “a small borderline advantage” for distant recurrence (20.9% vs 22.3%), he reported.

However, there was a significant benefit of bisphosphonates in bone recurrence in postmenopausal women (6.9% vs 8.4%; P = .0009), with no effect on nonbone recurrence.

There was no impact of bisphosphonates on local recurrence or cancer in the contralateral breast.

For distant recurrence, there was a 3.5% absolute benefit in postmenopausal women (18.4% vs 21.9%; P = .0003); for distant recurrence, there is was a significant improvement of 2.9% in bone recurrence (5.9% vs 8.8%; P < .00001).

There was no significant reduction in first distant recurrence outside bone, and risk reductions were similar, irrespective of estrogen-receptor status, node status, or use or not of chemotherapy.

“Adjuvant bisphosphonates reduce bone metastases and improve survival in postmenopausal women,” concluded Dr. Coleman. “We have statistical security in this result, with a 34% reduction in the risk of bone recurrence (P = .00001), and a 17% — or 1 in 6 — reduction in the risk of breast cancer death (P =.004).”

The analysis struck a clear line between pre- and postmenopausal women — something that was revealed in a subgroup analysis the AZURE trial, which Dr. Coleman was involved in (N Engl J Med. 2011;365:1396-1405).

Because of this, he was asked about the validity of basing the current analysis on the AZURE hypothesis-generating population.

“We repeated the analysis without the AZURE patients, because they are the hypothesis-generating population, and the P values and risk reductions did not change,” he explained.

Source: Medscape Medical News at http://www.medscape.com/viewarticle/817787#vp_1

Updated on 10/20/2015: Other articles for reference on Bisphosphonates and Metastasis

Clin Exp Metastasis. 2015 Oct;32(7):689-702. doi: 10.1007/s10585-015-9737-y. Epub 2015 Aug 1.

Human breast cancer bone metastasis in vitro and in vivo: a novel 3D model system for studies of tumour cell-bone cell interactions.

Author information

  • 1Academic Unit of Clinical Oncology, Department of Oncology, Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffield, S10 2RX, UK.
  • 2Department of Human Metabolism, Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffield, S10 2RX, UK.
  • 3Academic Unit of Clinical Oncology, Department of Oncology, Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffield, S10 2RX, UK. p.d.ottewell@sheffield.ac.uk.

Abstract

Bone is established as the preferred site of breast cancer metastasis. However, the precise mechanisms responsible for this preference remain unidentified. In order to improve outcome for patients with advanced breast cancer and skeletal involvement, we need to better understand how this process is initiated and regulated. As bone metastasis cannot be easily studied in patients, researchers have to date mainly relied on in vivo xenograft models. A major limitation of these is that they do not contain a human bone microenvironment, increasingly considered to be an important component of metastases. In order to address this shortcoming, we have developed a novel humanised bone model, where 1 × 10(5) luciferase-expressing MDA-MB-231 or T47D human breast tumour cells are seeded on viable human subchaodral bone discs in vitro. These discs contain functional osteoclasts 2-weeks after in vitro culture and positive staining for calcine 1-week after culture demonstrating active bone resorption/formation. In vitro inoculation of MDA-MB-231 or T47D cells colonised human bone cores and remained viable for <4 weeks, however, use of matrigel to enhance adhesion or a moving platform to increase diffusion of nutrients provided no additional advantage. Following colonisation by the tumour cells, bone discs pre-seeded with MDA-MB-231 cells were implanted subcutaneously into NOD SCID mice, and tumour growth monitored using in vivo imaging for up to 6 weeks. Tumour growth progressed in human bone discs in 80 % of the animals mimicking the later stages of human bone metastasis. Immunohistochemical and PCR analysis revealed that growing MDA-MB-231 cells in human bone resulted in these cells acquiring a molecular phenotype previously associated with breast cancer bone metastases. MDA-MB-231 cells grown in human bone discs showed increased expression of IL-1B, HRAS and MMP9 and decreased expression of S100A4, whereas, DKK2 and FN1 were unaltered compared with the same cells grown in mammary fat pads of mice not implanted with human bone discs.

Cancer. 2000 Jun 15;88(12 Suppl):2979-88.

Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma.

Abstract

BACKGROUND:

Bone, which abundantly stores a variety of growth factors, provides a fertile soil for cancer cells to develop metastases by supplying these growth factors as a consequence of osteoclastic bone resorption. Accordingly, suppression of osteoclast activity is a primary approach to inhibit bone metastasis, and bisphosphonate (BP), a specific inhibitor of osteoclasts, has been widely used for the treatment of bone metastases in cancer patients. To obtain further insights into the therapeutic usefulness of BP, the authors studied the effects of BP on bone and visceral metastases in animal models of metastasis.

METHODS:

The authors used two animal models of breast carcinoma metastasis that they had developed in their laboratory over the last several years. One model uses female young nude mice in which inoculation of the MDA-MB-231 or MCF-7 human breast carcinoma cells into the left cardiac ventricle selectively develops osteolytic or osteosclerotic bone metastases, respectively. Another model uses syngeneic female mice (Balb/c) in which orthotopic inoculation of the 4T1 murine mammary carcinoma cells develops metastases in bone and visceral organs including lung, liver, and kidney.

RESULTS:

BP inhibited the development and progression of osteolytic bone metastases of MDA-MB-231 breast carcinoma through increased apoptosis in osteoclasts and breast carcinoma cells colonized in bone. In a preventative administration, however, BP alone increased the metastases to visceral organs with profound inhibition of bone metastases. However, combination of BP with anticancer agents such as uracil and tegafur or doxorubicin suppressed the metastases not only in bone but also visceral organs and prolonged the survival in 4T1 mammary tumor-bearing animals. Of interest, inhibition of early osteolysis by BP inhibited the subsequent development of osteosclerotic bone metastases of MCF-7 breast carcinoma.

CONCLUSIONS:

These results suggest that BP has beneficial effects on bone metastasis of breast carcinoma and is more effective when combined with anticancer agents. They also suggest that the animal models of bone metastasis described here allow us to design optimized regimen of BP administration for the treatment of breast carcinoma patients with bone and visceral metastases.

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Metabolic Genomics and Pharmaceutics, Vol. 1 of BioMed Series D available on Amazon Kindle


Metabolic Genomics and Pharmaceutics, Vol. 1 of BioMed Series D available on Amazon Kindle

Reporter: Stephen S Williams, PhD

 

Leaders in Pharmaceutical Business Intelligence would like to announce the First volume of their BioMedical E-Book Series D:

Metabolic Genomics & Pharmaceutics, Vol. I

SACHS FLYER 2014 Metabolomics SeriesDindividualred-page2

which is now available on Amazon Kindle at

http://www.amazon.com/dp/B012BB0ZF0.

This e-Book is a comprehensive review of recent Original Research on  METABOLOMICS and related opportunities for Targeted Therapy written by Experts, Authors, Writers. This is the first volume of the Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases.  It is written for comprehension at the third year medical student level, or as a reference for licensing board exams, but it is also written for the education of a first time baccalaureate degree reader in the biological sciences.  Hopefully, it can be read with great interest by the undergraduate student who is undecided in the choice of a career. The results of Original Research are gaining value added for the e-Reader by the Methodology of Curation. The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012.  All new articles on this subject, will continue to be incorporated, as published with periodical updates.

We invite e-Readers to write an Article Reviews on Amazon for this e-Book on Amazon.

All forthcoming BioMed e-Book Titles can be viewed at:

https://pharmaceuticalintelligence.com/biomed-e-books/

Leaders in Pharmaceutical Business Intelligence, launched in April 2012 an Open Access Online Scientific Journal is a scientific, medical and business multi expert authoring environment in several domains of  life sciences, pharmaceutical, healthcare & medicine industries. The venture operates as an online scientific intellectual exchange at their website http://pharmaceuticalintelligence.com and for curation and reporting on frontiers in biomedical, biological sciences, healthcare economics, pharmacology, pharmaceuticals & medicine. In addition the venture publishes a Medical E-book Series available on Amazon’s Kindle platform.

Analyzing and sharing the vast and rapidly expanding volume of scientific knowledge has never been so crucial to innovation in the medical field. WE are addressing need of overcoming this scientific information overload by:

  • delivering curation and summary interpretations of latest findings and innovations on an open-access, Web 2.0 platform with future goals of providing primarily concept-driven search in the near future
  • providing a social platform for scientists and clinicians to enter into discussion using social media
  • compiling recent discoveries and issues in yearly-updated Medical E-book Series on Amazon’s mobile Kindle platform

This curation offers better organization and visibility to the critical information useful for the next innovations in academic, clinical, and industrial research by providing these hybrid networks.

Table of Contents for Metabolic Genomics & Pharmaceutics, Vol. I

Chapter 1: Metabolic Pathways

Chapter 2: Lipid Metabolism

Chapter 3: Cell Signaling

Chapter 4: Protein Synthesis and Degradation

Chapter 5: Sub-cellular Structure

Chapter 6: Proteomics

Chapter 7: Metabolomics

Chapter 8:  Impairments in Pathological States: Endocrine Disorders; Stress

                   Hypermetabolism and Cancer

Chapter 9: Genomic Expression in Health and Disease 

 

Summary 

Epilogue

 

 

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Archives of Medicine (AOM) to Publish from “Leaders in Pharmaceutical Business Intelligence (LPBI)” Open Access On-Line Scientific Journal http://pharmaceuticalintelligence.com

Reporter: Aviva Lev-Ari, PhD, RN

From our series on Calcium and Cardiovascular Diseases: A Series of Twelve Articles in Advanced Cardiology

AOM Editor-in Chief’s Article Selection and Assignment of manuscript number: iMedPub Journals includes the following and is updated as soon as additional selections are made

Part I:

Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

  

Part II: has been been assigned the following manuscript number: iMedPub Journals-15-472

Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN

 

Part III:

Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD
 and Aviva Lev-Ari, PhD, RN

  

Part IV: has been been assigned the following manuscript number: iMedPub Journals-15-471

The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, ArterialSmooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

 

Part V: has been been assigned the following manuscript number: iMedPub Journals-15-516

Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

 

Part VI:

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

 

Part VII:

Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

  

Part VIII

Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism – Part VIII

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Part IX

Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor – Part IX

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Part X – has been been assigned the following manuscript number: iMedPub Journals-15-517

Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission – Part X

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Part XI

Sensors and Signaling in Oxidative Stress – Part XI

Larry H. Bernstein, MD, FCAP

 

Part XII

Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD)) – Part XII

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part XIII has been been assigned the following manuscript number: iMedPub Journals-15-471

Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

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