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Cell Research News – What’s to Follow?

Larry H. Bernstein, MD, FCAP, Reporter

Leaders in Pharmaceutical Intelligence

https://pharmaceuticalintelligence.com/2014/08/26/larryhbern/Cell_Research_News_-_What’s_to_Follow?

 

Stem Cell Research ‘Holy Grail’ Uncovered, Thanks to Zebrafish

By Estel Grace Masangkay

With help from the zebrafish, a team of Australian researchers has uncovered how
hematopoietic stem cells (HSC) renew themselves.

HSCs refers to stem cells present in the blood and bone marrow that are used 
for  the replenishment of the body’s supply of blood and immune cells – 

  • in transplants for leukemia and myeloma.
  • Stem cells have the potential to transform into vital cells

    including muscle, bone, and blood vessels.

Understanding how HSCs form and renew themselves has potential application in the
treatment of

  • spinal cord injuries
  • degenerative disorders
  • diabetes.

Professor Peter Currie, of the Australian Regen Med Institute at Victoria’s Monash
University, led a research team to discover a crucial part of HSC’s development. Using 
a high-resolution microscopy, Prof. Curie’s team 

  • caught zebrafish embyonic SCs on film as they formed. 
  • the researchers were studying muscle mutations in the aquatic animal.

“Zebrafish make ESCs in exactly the same way as humans do, but their embryos and
larvae develop free living, but the larvae are both free swimming and transparent, so one could see every cell in the body forming, including ESCs,” explained Prof. Currie.

The researchers noticed in films that a

  •  ‘buddy cell’ came along to help the ESCs form.

Called endotome cells, 

  • they aided pre-ESCs to turn into ESCs.  

Prof. Currie said that endotome cells act as helper cells for pre-ESCs , 

  • helping them progress to become fully fledged stem cells.

The team not only

  • identified some of the cells and signals 
  • required for ESC formation, but also 
  • pinpointed the genes required 
  • for endotome formation in the first place.

The next step for the researchers is to 

  • locate the signals present in the endotome cells 
  • that trigger ESC formation in the embryo. 

This may provide clues for developing

  • specific blood cells on demand for blood-related disorders. 

Professor Currie also pointed out the discovery’s potential for 

  • correcting genetic defects in the cell and 
  • transplanting them back in the body to treat disorders.

The team’s work was published in the international journal Nature.

 

Jell-O Like Biomaterial Could Hold Key to Cancer Cell Destruction

by Estel Grace Masangkay

Scientists from Penn State University reported that a biomaterial made of tiny 
molecules was able to attract and destroy cancer cells.

Professor Yong Wang and bioengineering faculty at Penn State, built the 
tissue-like biomaterial to accomplish what chemotherapy could not –

  • kill every cancer cell without leaving
  • the possibility of a recurrence.

Prof. Wang and team built polymers 

  • from tiny molecules called monomers. They
  • then wove the polymers into 3D networks 

called hydrogels. Hydrogel is soft and flexible, 
like Jell-O, and it contains a lot of water, and

  • can be safely put into the body, unlike 

other implants that the body often tries 

  • to get rid of through the immune response.

“We want to make sure the materials we are using are compatible in the body.”

The researchers 

  • attached aptamers to the hydrogels, 
  • which release bio-chemical signal-only molecules 
  • that draw in cancer cells. 

Once attracted, the cancer cells are entrapped in the Jell-O-like substance. 

What happens next is 

  • an oligonucleotide binds to the protein-binding site of the aptamer 
  • and triggers the release of anticancer drugs at the proper time.

“Once we trap the cancer cells, we can deliver anticancer drugs 

  • to that specific location to kill them. 

This technique would help avoid the need for systemic medications that kill not only cancer cells, but normal cells as well. Systemic chemotherapy drugs

  • make patients devastatingly sick and possibly 
  • leave behind cancer cells to wreak havoc another day

If our new technique has any side effects at all, it would be only local side 
effects and not whole-body systemic side effects,” explained Prof. Wang.

The initial results of the research were published by Prof. Wang in the 
Journal of the American Chemical Society in 2012. Prof. Wang also shared 
the latest results of his work at the Society for Biomaterials Meeting &
 Exposition in April this year.

 

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Author and Curator: Ritu Saxena, PhD

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What are cancer stem cells?

Cancer is a debilitating disease estimated to be responsible for about 7.6 million deaths in 2008 (Jemal A, et al, CA Cancer J Clin, Mar-Apr 2011;61(2):69-90). Thus, extensive research is underway to deal with the various types of cancer. The concept of cancer stem cells (CSC) has surfaced in in the past decade after identification and characterization of CSC-enriched populations in several different types of cancer (Lapidot T, et al, Nature, 17 Feb 1994;367(6464):645-8; Reya T, et al, Nature, 1 Nov 2001;414(6859):105-11;  Trumpp A and Wiestler OD, et al, Nat Clin Pract Oncol, Jun 2008;5(6):337-47). Although there has been lot of debate on the cell of origin of CSC, according to the classical concept CSC are defined by their functional properties.

Functional properties of CSC

  • CSCs are at the top of tumor hierarchy. Regenerative tissues follow a hierarchical organization with adult stem cells at the top maintaining tissues and normal adult cells during homeostasis and regeneration during cell loss from injury. Similarly, several tumors follow the hierarchy with CSC at the top. Hierarchical organization has been reported in several cancer types including but not limited to breast cancer, brain cancer, colon cancer, leukemia and pancreatic cancer (Lapidot T, et al, Nature, 17 Feb 1994;367(6464):645-8; Al-Hajj M, et al, PNAS USA, 1 Apr 200;100(7):3983-8; Singh SK, et al, Nature, 18 Nov 2004;432(7015):396-401; Dalerba P, et al, PNAS USA, 12 Jun 2007;104(24):10158-63; Hermann PC, et al, Cell Stem Cell, 13 Sep 2007;1(3):313-23).
  • CSCs possess unlimited self-renewal capacity similar to that of physiological stem cells and unlike other differentiated cell types within the tumor. Cancer stem cells can also generate non-CSC progeny that is comprised of differentiated cells and forms tumor bulk.
  • Some CSs exhibit quiescent or dormant stage. Although not observed in all CSC types, some CSCs have been found to shuttle between quiescent, slow-cycling, and active states. The CSCs in their dormant and slow-cycling stage are less likely to be affected by conventional anti-tumor therapies which generally target rapidly dividing cells. Dormant stage is exhibited even in adult stem cells and the dormant normal stem cells can regain cell division potential during tissue injury (Wilson A, et al, Cell,  12 Dec 2008;135(6):1118-29). Thus, it has been speculated that dormant CSC might be a reason for tumor relapse even after pathologic complete response is observed post therapy.
  • Some CSCs are resistant to conventional anti-cancer therapies. This leads to accumulation of CSC that might result in relapse after anti-cancer therapy. For instance, Li et al (2008) reported that CSC accumulated in the breast of women with locally advanced tumors after cytotoxic chemotherapy had eliminated the bulk of the tumor cells (Li X,et al, J Natl Cancer Inst, 7 May 2008;100(9):672-9). A similar observation was made by Oravecz-Wilson et al (2009) stating that despite remarkable responses to the tyrosine kinase inhibitor imatinib, CML patients show imatinib refractoriness because leukemia stem cells in CML are resistant tyrosine kinase (Oravecz-Wilson KI, et al, Cancer Cell, 4 Aug 2009;16(2):137-48).
  • The CSC niche. CSC functional traits might be sustained by this microenvironment, termed “niche”. The niche is the environment in which stem cells reside and is responsible for the maintenance of unique stem cell properties such as self-renewal and an undifferentiated state. The heterogeneous populations which constitute a niche include both stem cells and surrounding differentiated cells. The necessary intrinsic pathways that are utilized by this cancer stem cell population to maintain both self-renewal and the ability to differentiate are believed to be a result of the environment where cancer stem cells reside. (Cabarcas SM, et al, Int J Cancer, 15 Nov 2011;129(10):2315-27). For instance, properties of CSC in glioma in a mouse xenograft model were maintained by vascular endothelial cells (Calabrese C, et al, Cancer Cell, Jan 2007;11(1):69-82). Several molecules including interleukin 6 have been observed to play a role in tumor proliferation and hence, participate in maintaining tumorigenic and self-renewal potential of CSC. Moreover, the CSC niche might not only regulate CSCs traits but might also directly provide CSC features to non-CSC population.

What is the origin of CSC?

According to current thinking, CSC result from epithelial-mesenchymal transition (EMT) when cells switch from a polarized epithelial to a non-polarized mesenchymal cell type with stem cell properties, including migratory behavior, self-renewal and generation of differentiated progeny, and reduced responsiveness to conventional cancer therapies (Scheel C and Weinberg RA, Semin Cancer Biol, Oct 2012;22(5-6):396-403; Crews LA and Jamieson CH, Cancer Lett, 17 Aug 2012). Evidence is accumulating that cancers of distinct subtypes within an organ may derive from different ‘cells of origin’. The tumor cell of origin is the cell type from which the disease is derived after it undergoes oncogenic mutation. It might take a series of mutations to achieve the CSC phenotype (Visvader JE, Nature, 20 Jan 2011;469(7330):314-22). Also, CSCs have been reported to originate from stem cells in some cases.

Biomarkers for CSC

CSC targeting therapy could either eliminate CSCs by either killing them after differentiating them from other tumor population, and/or by disrupting their niche. Efficient eradication of CSCs may require the combined ablation of CSCs themselves and their niches. Identifying appropriate biomarkers of CSC is a very important aim for CSCs to be useful as targets of anti-cancer therapies in order to possibly prevent relapse. Using cell surface markers, CSCs have been isolated and purified from cancers of breast, brain, thyroid, cervix, lung, blood (leukemia), skin (melanoma), organs of the gastrointestinal and reproductive tracts, and the retina. The challenge, however, is that CSCs share similar markers with normal cells which makes CSCs targeting difficult as it would harm normal cells in the process. More recently, advanced techniques such as signal sequence trap (SST) PCR screening methods have been developed to identify a leukemia-specific stem cell marker (CD96). After a small subset of human AML cells displayed tumorigenic properties, Leukemia Stem Cells (LSCs) were identified as leukemia cells with CD23+/CD38+ markers. These cells closely resemble hematopeotic stem cells (HSCs) (Bonnet D and Dick JR, Nat Med, Jul 1997;3(7):730-7). In solid tumors, a significant discovery was made when CSCs in breast cancer were identified within the ESA+/CD44+/CD24low-neg population of mammary pleural effusion and tumor samples (Al-Hajj M, et al, PNAS USA, 1 Apr 200;100(7):3983-8).

After these two landmark publications, CSCs were identified in many more solid and hematopoietic human tumors as well. In addition, within a tumor type, CSC-enriched populations display heterogeneity in markers. For example, only 1% of breast cancer cells simultaneously express both reported CSC phenotypes ESA+/CD44+/

CD24low-neg and ALDH-1+ (Ginestier C, et al, Cell Stem Cell, 1 Nov 2007;1(5):555-67). The discrepancy might be due to different techniques used to identify the markers and also a reflection of the molecular heterogeneity within the tumors. Recent advances in genome wide expression profiling studies have led to the identification of different subtypes in a particular type of cancer. Breast cancer was recently classified into different subtypes and this genetic heterogeneity is likely paralleled by a heterogeneous CSC complexity.

Conclusion

A lot of research is currently underway on various aspects of CSCs including biomarker identification, cell of origin, and clinical trials targeting CSC population in cancer. The concept of CSCs has evolved quite a bit since their discovery. Recently, identification of high genetic heterogeneity within a tumor has been in focus and subsequently it has been observed that several CSC clones can coexist and compete with each other within a tumor. Adding complexity to their identity is the fact that CSCs may have unstable phenotypes and genotypes. Taken together, the dynamics associated with CSCs makes it difficult to identify reliable and robust biomarkers and develop efficient targeted therapies. Thus, a major thrust of research should be to focus on the unfolding of the dynamic identity of CSCs in tumor types and at different that might lead to the identification and targeting of highly specific CSCs biomarkers.

Reference

Jemal A, et al, CA Cancer J Clin, Mar-Apr 2011;61(2):69-90

Reya T, et al, Nature, 1 Nov 2001;414(6859):105-11

Trumpp A and Wiestler OD, et al, Nat Clin Pract Oncol, Jun 2008;5(6):337-47

Lapidot T, et al, Nature, 17 Feb 1994;367(6464):645-8

Singh SK, et al, Nature, 18 Nov 2004;432(7015):396-401

Dalerba P, et al, PNAS USA, 12 Jun 2007;104(24):10158-63

Hermann PC, et al, Cell Stem Cell, 13 Sep 2007;1(3):313-23

Wilson A, et al, Cell,  12 Dec 2008;135(6):1118-29

Li X,et al, J Natl Cancer Inst, 7 May 2008;100(9):672-9

Oravecz-Wilson KI, et al, Cancer Cell, 4 Aug 2009;16(2):137-48

Cabarcas SM, et al, Int J Cancer, 15 Nov 2011;129(10):2315-27

Calabrese C, et al, Cancer Cell, Jan 2007;11(1):69-82

Scheel C and Weinberg RA, Semin Cancer Biol, Oct 2012;22(5-6):396-403

Crews LA and Jamieson CH, Cancer Lett, 17 Aug 2012

Visvader JE, Nature, 20 Jan 2011;469(7330):314-22

Bonnet D and Dick JR, Nat Med, Jul 1997;3(7):730-7

Al-Hajj M, et al, PNAS USA, 1 Apr 200;100(7):3983-8

Ginestier C, et al, Cell Stem Cell, 1 Nov 2007;1(5):555-67

Baccelli I and Trumpp AJ, Cell Biol, 6 Aug 2012;198(3):281-93

Zhao L, et al, Eur Surg Res, 2012;49(1):8-15

Pharmaceutical Intelligence posts:

https://pharmaceuticalintelligence.com/2012/08/15/to-die-or-not-to-die-time-and-order-of-combination-drugs-for-triple-negative-breast-cancer-cells-a-systems-level-analysis/

Authors: Anamika Sarkar, PhD and Ritu Saxena, PhD

https://pharmaceuticalintelligence.com/2013/03/07/the-importance-of-cancer-prevention-programs-new-perceptions-for-fighting-cancer/ Author: Ziv Raviv, PhD

https://pharmaceuticalintelligence.com/2013/03/03/treatment-for-metastatic-her2-breast-cancer/ Reporter: Larry H Bernstein, MD

https://pharmaceuticalintelligence.com/2013/03/02/recurrence-risk-for-breast-cancer/

Larry H Bernstein, MD

https://pharmaceuticalintelligence.com/2013/02/14/prostate-cancer-androgen-driven-pathomechanism-in-early-onset-forms-of-the-disease/ Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/15/exploring-the-role-of-vitamin-c-in-cancer-therapy/ Curator: Ritu Saxena, PhD

https://pharmaceuticalintelligence.com/2013/01/12/harnessing-personalized-medicine-for-cancer-management-prospects-of-prevention-and-cure-opinions-of-cancer-scientific-leaders-httppharmaceuticalintelligence-com/ Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/10/the-molecular-pathology-of-breast-cancer-progression/ Author and reporter: Tilda Barliya PhD

https://pharmaceuticalintelligence.com/2012/11/30/histone-deacetylase-inhibitors-induce-epithelial-to-mesenchymal-transition-in-prostate-cancer-cells/ Reporter and Curator: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2012/10/22/blood-vessel-generating-stem-cells-discovered/ Reporter: Ritu Saxena, PhD

https://pharmaceuticalintelligence.com/2012/10/17/stomach-cancer-subtypes-methylation-based-identified-by-singapore-led-team/ Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/09/17/natural-agents-for-prostate-cancer-bone-metastasis-treatment/ Reporter: Ritu Saxena, PhD

https://pharmaceuticalintelligence.com/2012/08/28/cardiovascular-outcomes-function-of-circulating-endothelial-progenitor-cells-cepcs-exploring-pharmaco-therapy-targeted-at-endogenous-augmentation-of-cepcs/ Aviva Lev-Ari, PhD, RN

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Author and Reporter: Ritu Saxena, Ph.D.

Introduction

Blood vessels arise from endothelial precursors that are thin, flat cells lining the inside of blood vessels forming a monolayer throughout the circulatory system. ECs are defined by specific cell surface markers including CD31, CD34, CD105, VE-cadherin, vascular endothelial growth factor receptor 1 [VEGFR-1], VEGFR-2, Tie-1, Tie-2) that characterize their phenotype. Angiogenesis is the growth of new blood vessels from preexisting ones and is required for growth and repair. Malignancy is a pathological scenario that requires angiogenesis. The definite cellular origin of adult blood vessel-forming cells necessary for neoangiogenesis has been unknown. Weissman and fellow coworkers in their previous work indicated that the address of these cells might be local, residing in non-circulating tissue. Also, very low numbers of cells with endothelial characteristics and high proliferative potential have been reported in umbilical cord blood or in peripheral blood. The function of circulating endothelial progenitor cells and pharmacotherapy targeted at the      endogenous augmentation of these cells for their use in cardiovascular repair has been discussed in detail in a post authored by Aviva Lev-Ari on August 28, 2012.

Research

Scientists at the University of Helsinki, Finland, wanted to find out if there exists a rare vascular endothelial stem cell (VESC) population that is capable of producing very high numbers of endothelial daughter cells, and can lead to neovascular growth in adults.  They were not only able to define the characteristic cells responsible for giving rise of blood vessels in adults, but took a leap forward by generating blood vessels from a single cells from the VESC population. (Figure:  VESCs discovered that reside at the blood vessel wall endothelium. These are a small population of CD117+ ECs capable of self-renewal.  Image Courtesy: Fang et al, 2012).

The VESCs, as explained by the Fang and coworkers, reside in the blood vessel wall endothelium and constitute a small subpopulation within CD117+ (c-kit+) endothelial cells (ECs). These cells are capable of undergoing clonal expansion unlike the surrounding ECs that bear limited proliferating potential. VESC discovered in this study were found to a have a certain characteristic phenotype defined by the presence of a few surface proteins. The authors utilized the technique of FACS (Fluorescence Activated Cell Sorting) to isolate the cells capable of undergoing clonal expansion. The sorting was performed against endothelial-specific protein markers CD31 and CD15, and against CD117 and Sca-1 molecules that are expressed by many adult stem cell types including hematopoietic stem cells (HSCs) and prostate and mammary gland stem cells. The experimental results defined the surface characteristics or the phenotype of the isolated cells to be lin2CD31+CD105+Sca1+CD117+A.  A single VESC cell isolated from the endothelial population was able to generate functional blood vessels that connected to host circulation after transplantation in mouse. In cell culture, these cells were shown to generate tens of millions of daughter endothelial cells. Also, within cell culture, the isolated VESCs showed long-term self-renewal properties, bearing similarity to adult stem cells. The self-renewal capacity of VESCs was evident even in vivo, when the ‘isolated’ ECs containing VESCs retained the capacity to generate functional blood vessels during serial transplantations. The transplanted ECs were monitored with the help of Green Fluorescent protein (GFP). Fluorescent blood vessels were observed in secondary, tertiary, and quaternary transplants providing direct evidence that the GFP-tagged ECs contained VESCs with self-renewal capacity.

Furthermore, the cell culture and animal experiment results were supported by the observation that abundant CD117+ ECs were discovered in human malignant melanomas and invasive breast cancer samples.

Research relevance

The discovery of VESCs is seminal and could be of tremendous therapeutic potential. It could be useful in the following ways leading way for related research endeavors including-

  • Cell-based therapies: VESCs could be used in cell-based therapies for cardiovascular repair to restore tissue vascularization i.e., the daughter cells arising from VESCs at the target site could assist in repair by generation of  neoangiogenic ECs required for the formation of blood vessels.
  • Therapeutic target: VESCs could serve as a possible cellular and molecular target to restrain angiogenesis by inhibiting endothelial-cell proliferation thereby blocking cancer progression.

Sources:

Fang S et al, Generation of Functional Blood Vessels from a Single c- kit + Adult Vascular Endothelial Stem Cell. PLoS Biol. 2012;10(10):e1001407. http://www.ncbi.nlm.nih.gov/pubmed/23091420

News Brief: http://www.business-standard.com/generalnews/news/scientists-discover-new-blood-vessel-generating-cells/69329/

Related reading:

Cardiovascular and endothelial cells

Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation Curator, Author,Writer, Reporter: Larry Bernstein, MD, FCAP

Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs Author and Curator: Aviva Lev-Ari, PhD, RN

Vascular Medicine and Biology: Macrovascular Disease – Therapeutic Potential of cEPCs Curator and Author: Aviva Lev-Ari, PhD, RN

Repair damaged blood vessels in heart disease, stroke, diabetes and trauma: Cellular Reprogramming amniotic fluid-derived cells into Endothelial Cells Reporter: Aviva Lev-Ari, PhD, RN

Stem cells in therapy

A possible light by Stem cell therapy in painful dark of Osteoarthritis” – Kartogenin, a small molecule, differentiates stem cells to chondrocyte, healthy cartilage cells Author and Reporter: Anamika Sarkar, Ph.D and Ritu Saxena, Ph.D.

Human embryonic pluripotent stem cells and healing post-myocardial infarction Author: Larry H. Bernstein, MD

Stem cells create new heart cells in baby mice, but not in adults, study shows Reporter: Aviva Lev-Ari, PhD, RN

Stem cells for the rescue of mitochondrial dysfunction in Parkinson’s disease Reporter: Ritu Saxena, Ph.D.

Stem Cell Research — The Frontier is at the Technion in Israel Reporter: Aviva Lev-Ari, PhD, RN

Research articles by MA Gaballa, PhD

Harris DT, Badowski M, Nafees A, Gaballa MA. The potential of Cord Blood Stem Cells for Use in Regenerative Medicine. Expert Opinion in Biological Therapy 2007. Sept 7(9): 1131-22.

Furfaro E, Gaballa MA. Do adult stem cells ameliorate the damaged myocardium?. Human cord blood as a potential source of stem cells. Current Vascular Pharmacology 2007, 5; 27-44.

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