Posts Tagged ‘TGF-β/Smad4 signaling’

Author: Tilda Barliya PhD

Metastasis is a complex series of steps in which cancer cells leave the original tumor site and migrate to a distant organ. Certain cancers tend to spread to specific organ sites; however, the underlying mechanism is not completely understood. After lymph nodes, the liver is the most common site for colorectal cancer metastasis, and liver metastasis is a common cause of cancer-related mortality. Understanding the mechanisms and genetic alterations that predispose to the metastatic phenotype in colorectal cancer is imperative for early detection, prevention and treatment (1). Studies reveal that genomic instability in cancer cells leads to cellular heterogeneity, which may guide tumor cell aggression and specific organ colonization during the metastatic process.

Nat Clin Pract Oncol. 2008;5(4):206-219.

In 2008, Patricia S Steeg, Dan Theodorescu have published a great overview on the cancer metastases (1a).  Figure 1 represents Molecular distinctions between primary colorectal carcinomas and their liver metastases.

Studies have identified distinct expression trends at the RNA or protein levels in primary tumors and metastases, including genes that control metastasis (MTA1, N-Wasp, NCAML1), extracellular matrix function (fibronectin, collagens), microtubule dynamics (stathmin), transcription (Snail), drug-processing enzymes (DPD, TS) and kinases (Yes1).

It is worth mentioning that not every overexpressed or mutated gene is directly and primarily correlated with tumor metastases.

In order to answer this question, Ding Q and colleagues (1b) have done a great job identifying the gene expression signature for colorectal cancer liver metastases. Using an orthotopic colorectal cancer mouse model and transcriptomic microarray analysis, they found that 4 major genes are essential in mediating CRC-liver metastasesAPOBEC3GCD133LIPC, and S100P.

APOBEC3G– Is an apolipoprotein B mRNA-editing enzyme that has been suggested to play a role in the innate anti-viral immune system. Notably, this is the first time it has been shown that APOBEC3G, a gene involved in RNA editing, is able to promote tumor metastasis. APOBEC3G may downregulate miR-29 expression and hamper miR-29 activity in repressing MMP2.

CD133 – is a glycoprotein that is expressed in hematopoetic stem cells, endothelial progenitor cells, intestinal stem cells as well as saeveral types of tumor stem cells. It was related to a high incidence of metastasis in cholangiocarcinoma and melanoma has been indicated, However, questions regarding how CD133 is involved in metastasis and in which cancer stages, how CD133 expression is regulated, and what controls the transition of CD133+ to CD133– cells remain to be addressed.

LIPC –  is Hepatic Triacylglycerol Lipase. It is expressed in the liver and adrenal gland. One of the principal functions of hepatic lipase is to convert intermediate-low density lipoprotein (IDL) to low-density lipoprotein (LDL). A recent study also implicates a role for monoacylglycerol lipase in promoting tumor growth, migration, and invasion, as this lipase translates lipogenic phenotype to oncogenic signals in tumor cells.

S100P –  S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation.  This protein may paly a role in the etiology of prostate cancer.

The authors (1b) found that overexpressing of these 4 genes increases the invasion and migration abilities of the SW620-control cells (= lymph node metastatic cell line) in vitro and also significantly enhances the frequency of hepatic metastasis in vivo (1b).

To determine the clinical correlation of our identified gene signatures with colorectal cancer hepatic metastasis, the authors examined the protein levels of APOBEC3GCD133LIPC, and S100P in 7 freshly isolated human colorectal cancer hepatic metastatic tumors and 7 nonmetastatic primary colorectal carcinomas. We showed that expression levels of these 4 genes are significantly increased in the metastatic tumors compared with the nonmetastatic primary tumors (1b).

Knocking down either one of these genes was not sufficient to decrease the liver metastasis rate in the orthotopic animal model, if compared with knocking down all 4 genes, indicating that the process of liver metastasis may require the cooperation/synergism of the 4 genes.

EGFR  was also identified to be a potential key player for liver metastases. There is somewhat conflicting data regarding the importance or use of EGF as an indicator for liver metasteses.  While some clinical protocols suggest patients with KRAS wild-type should be considered for combination therapy with EGFR inhibitors, because this strategy has led to promising results with improved R0 resection (2), others have shown that EGFR expression in the primary tumor site was not predictive of its level in the metastasis. EGFR expression levels in the primaries and in the metastases do not appear to be useful prognostic markers (3).

Additionally, recent studies also revealed that certain genes and signaling pathways might play a role in colon cancer liver metastasis. Metastasis-associated in colon cancer-1 (Macc1) was identified as a key regulator of HGF-MET signaling and is able to enhance colon cancer cell migration in vitro and liver metastasis in mouse model. TGF-β/Smad4 signaling was found to suppresses colon cancer metastasis in mice and the balance between Smad4/Smad7 and the TGF-β pathway in colorectal cancer may be critical for the metastatic process (1b).

Wulfkuhle and colleagues recently published an innovative study comparing the proteomic profiles of hepatic metastases generated by tumors from different primary organ sites. They strongly suggest that the microenviornment of the host organ plays a pivotal role in the activation of specific survival pathways (4).

The role of microenvironment and heterogeneity is reviewed by Bert Vogelstein  and colleagues in their outstanding paper on the Cancer Genome Landscape (5). They outline the multiplex orchestra of genes and their mutations that play role in cancer initiation, progressions and invasion into new metastatic niches,

In summary:

Many of the molecular pathways that promote tumorigenesis also promote metastasis and are important in the treatment of both aspects of cancer progression. This is a multiplex process that involves alternations/mutations in many genes and metastases, much like primary tumors, varies within a single patient and between patient.  The biology of liver metastases has been intensively investigated and several  genes where identified yet, one must remember that these set of gene may be true to one source of primary tumor origin and not not to another.  From a technical standpoint, the development of new and improved methods for early detection and prevention will not be easy, but there is no reason to assume that it will be more difficult than the development of new therapies aimed at treating widely metastatic disease. For further review on concurrent treatments for colorectal liver metastases, please go to liver metastases_treatments (I)


1a. Patricia S Steeg, Dan Theodorescu. Metastasis: A Therapeutic Target for Cancer. Nat Clin Pract Oncol. 2008;5(4):206-219.

1b. Qingqing Ding, Chun-Ju Chang, Xiaoming Xie, Weiya Xia, Jer-Yen Yang ,Shao-Chun Wang, Yan Wang, Jiahong Xia, Libo Chen, Changchun Cai, Huabin Li, Chia-Jui Yen, Hsu-Ping Kuo, Dung-Fang Lee, Jingyu Lang, Longfei Huo,Xiaoyun Cheng, Yun-Ju Chen, Chia-Wei Li, Long-Bin Jeng, Jennifer L. Hsu, Long-Yuan Li , Alai Tan, Steven A. Curley, Lee M. Ellis, Raymond N. DuBois and Mien-Chie Hung. APOBEC3G promotes liver metastasis in an orthotopic mouse model of colorectal cancer and predicts human hepatic metastasis. J Clin Invest. 2011;121(11):4526–4536. doi:10.1172/JCI45008.

2. Macelo R.S Cruz and Gilberto de Lima Lopes. Colon Cancer Liver Metastasis: Addition of Antiangiogenesis or EGFR Inhibitors to Chemotherapy. Current Colorectal Cancer Reports March 2013, 9(1); pp 68-73.

3. Nirit Yarom N, Celia Marginean, Terence Moyana, Ivan Gorn-Hondermann , H. Chaim Birnboim, Horia Marginean, Rebecca C. Auer, Micheal Vickers, Timothy R. Asmis, Jean Maroun, Derek Jonker EGFR expression variance in paired colorectal cancer primary and metastatic tumors. Cancer Biol Ther 2010 Sep 1;10(5):416-421.

4. Wulfkuhle J, Espina V, Liotta L, Petricoin E. Genomic and proteomic technologies for individualisation and improvement of cancer treatment. Eur J Cancer. 2004 Nov;40(17):2623-2632.

5. Bert Vogelstein, Nickolas Papadopoulos, Victor E. Velculescu, Shibin Zhou, Luis A. Diaz Jr., Kenneth W. Kinzler. Cancer Genome Landscapes. Science 29 March 2013:  Vol. 339 no. 6127 pp. 1546-1558

Other articles from our open access journal:

I. By Tilda Barliya PhD. Liver metastases_treatments.

II. By Tilda Barliya PhD. Cancer metastasis.

III. By. Tilda Barliya PhD. Colon Cancer.

IV. By. Stephen J. Williams. Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing.


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