A closer look into metastatic process may provide clues to better survival for cancer patients

In most cancer types, a large percentage of patients succumb to metastatic disease instead of complications related to the original primary tumor.

ai???That is why addressing the problem of metastasis is of utmost importance for the successful treatment and improved survival of cancer patients,ai??? urged researchers Lefteris C. Zacharia and Vasiliki Gkretsi, both respectively from Department of Life and Health Sciences at Greeceai??i??s University of Nicosia and Department of Biomedical Research and Technology at Centre for Research and Technology-Hellas.


Cancer cells in culture from human connective tissue, illuminated by darkfield amplified contrast, at a magnification of 500x.

Metastasis is a complex process that ultimately leads to cancer cell spreading through tissues in the whole body. ai???During the metastatic process, as cancer cells accumulate mutations or other molecular signals, they become more malignant and tend to easily lose contact with the extracellular matrix (ECM) and neighboring cells within the primary tumor. Hence, they start to invade surrounding tissues,ai??? explained Zacharia and Gkretsi in a review article in the journal Advances in Modern Oncology Research.

ai???Both cell-cell adhesion and cell-ECM adhesions get deregulated promoting cancer cell aggressiveness. In fact, communication between cells and the ECM and between neighboring cells is severely disrupted in more aggressive and invasive cells. Hence ECM, integrins and the ECM-associated adhesion proteins play a critical role in this process,ai??? the authors added.

Their review focuses on interesting and novel molecules at the cell-ECM adhesion sites and the moleculesai??i?? critical involvement in cancer cell metastasis, based on data from experiments performed in vitro in breast cancer and hepatocellular carcinoma (HCC) cell lines as well as human breast cancer tissue samples.


The malignant breast cancer cells metastasized to the liver. A cluster of the cancer-cells with their brown-staining cytoplasm is within a portal tract of the liver (monoclonal antibody b1.1, abc immunoperoxidase method, hematoxylin counterstain, x500). Source: National Cancer Institute

ai???Several novel molecules at cell-ECM adhesion sites have been implicated in cancer cell progression and have been recently shown to be deregulated in cancer cell metastasis,ai??? according to Zacharia and Gkretsi. Migfilin, for instance, is a novel LIM domain containing protein that is present both at cell-ECM and cell-cell adhesions.

ai???Migfilin has been associated with various types of cancer although its role has not been extensively studied,ai??? noted the authors. ai???Work from our group has shown that migfilin was also significantly reduced in human breast cancer samples compared to normal adjacent tissue, indicating an involvement of the protein in cancer progression. Along the same line, migfilin was also examined in advanced-stage serous ovarian carcinoma and was found to have significantly lower expression in primary carcinomas and solid metastases compared to effusions.ai???


This illustration titled ai???How Cancer Spreadsai??? explains the process of metastasis. Once metastatic cells are attached to the basement membrane (a physical barrier that seperates tissue components), they break through with the help of an enzyme called type IV collagenase. Cancer cells then move through the blood stream enabling them to spread to other parts of the body. A secondary tumor may form at another site in the body. Source: National Cancer Institute

As metastasis is a fundamental biological behavior of HCC and the main cause of treatment failure, the researchers also tested the in vitro role of migfilin in two liver cell lines that differ in terms of their metastatic potential and studied the effect of gene silencing on basic signaling pathways and functional cellular properties related to the metastatic potential of the cells.

ai???We found that migfilin was elevated in the more invasive HepG2 cells compared to the less invasive Alexander cells (hepatoma cell line PLC/ PRF/5) both at the mRNA and protein level, indicating a possible contribution of the protein to the aggressive phenotype of HepG2 cells. Moreover, gene silencing of migfilin led to upregulation of proteins involved in actin reorganization such as the two main forms of phosphorylated VASP (Ser157 and Ser239) in HepG2 cells, and Fascin-1 and Rho kinase (ROCK-1) in both cell lines,ai??? explained Zacharia and Gkretsi.

Increased expression of these molecules led to increased actin polymerization and stabilization, according to the authors, which thus resulted in less available monomeric actin for cell migration or invasion ultimately contributing to reduced cell migration. Indeed, migfilin depletion led to reduced cell invasion, indicating that migfilin promotes the metastatic phenotype of HepG2 cells.

In fact, this is in accordance with previous studies showing migfilin to be crucial for cell migration in a variety of cell types where it was shown that its depletion impairs cell migration, according to Zacharia and Gkretsi. As migfilin has been previously shown to link the cell-matrix adhesions to the actin cytoskeleton, the migratory defect induced by the loss of migfilin is probably caused, at least in part, by the impaired connection between cell-ECM adhesions and the actin cytoskeleton.


Notably, the fact that elimination of migfilin severely impaired HepG2 cell invasion while at the same time increasing cell proliferation ai???indicates that migfilin has a dual function in HCC cells activating different signaling pathways perhaps through interaction with different binding partners,ai??? wrote the researchers.

This could provide an explanation as to why its role in cancer is not strictly defined but greatly depends upon the type of cancer. Nevertheless, evidence suggests that migfilin is worth being assessed as a therapeutic target for cancer cell metastasis for a number of cancer types, according to Zacharia and Gkretsi.

ai???We conclude that these cell-ECM adhesion proteins tend to function as adaptor proteins forming multiple protein-protein interactions at the cell-ECM adhesion sites, thus conferring different effects on different cancer cell types,ai??? they noted.


Co-authors Zacharia (R) and Gkretsi (L)

ai???In most cases, they promote cell adhesion, cell invasion and apoptosis, all of which are important aspects of cancer cell metastasis. Therefore, more research is needed involving more human samples in order to evaluate their use as potential biomarkers of metastasis and perhaps, even potential targets for anticancer therapy,ai??? Zacharia and Gkretsi concluded.

The article appears in open access peer-reviewed journal of Advances in Modern Oncology Research and is available at www.advmodoncolres.com.