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Thursday May 21st, 2009

Oxaliplatin Promotes the Survival of Drug-Resistant Colon Tumor Cells

Dr. Elisabet Ametller and Dr. Vanessa Almendro at Hospital Clínic

Oxaliplatin is a drug that is widely used to treat colon cancer, but its efficacy is limited by the development of resistance to chemotherapy of the tumor cells. The chemoresistant cells undergo molecular changes that protect them from the cell death induced by the drugs, thus re-establishing the processes of tumor progression. An article published in PLoS One analyzes the role of the metalloproteinase, MMP7, in the resistance mechanisms of these cells and its effect on the Fas receptor involved in promoting cell death by apoptosis. This study was directed by Dr. Vanessa Almendro of the department of medical oncology at Hospital Clínic-IDIBAPS and by Dr. Pere Gascón, and involved the collaboration of Dr. Elisabet Ametller, among others. The results show that, in colon cancer cell lines, MMP7 is directly related to the acquisition of resistance to oxaliplatin and its inhibition re-establishes sensitivity to the drug due to an increase in the Fas receptor. Furthermore, the authors observed that, surprisingly, the Fas receptor undergoes changes in functionality in cells resistant to oxaliplatin, leading it to induce survival signals instead of apoptotic signals.
Many tumor cells survive treatment during tumor progression by reducing their sensitivity to cell death induced by Fas, a membrane protein that initiates an apoptosis pathway when activated by its natural ligand (FasL). The matrix metalloproteinases, including MMP7, affect the Fas/FasL pathway. They are enzymes associated with different types and stages of cancer. They promote metastasis and tumor growth by means of a large variety of mechanisms that allow tumor cells to evade immune responses and thus increase survival of the tumor and allow it to spread. It has been observed in patients with advanced colon cancer that MMP7 is a prognostic factor for shorter survival, as the enzyme affects the response of the tumor cells to chemotherapy.

Different lines of colon cancer cells were used in the study and three different lines were developed from these that were resistant to oxaliplatin. To achieve this, the cells were exposed to increasing concentrations of the drug over a period of 5 months. The study shows that the overexpression of MMP7 is a direct result of acquiring resistance to oxaliplatin, thus confirming the hypothesis regarding its role in the development of this resistance. Because MMP7 promotes survival of the tumor, the drug also induces the expression of this enzyme in both normal and resistant tumor cells. This constitutes a paradox, as a drug designed to induce cell death is also capable of inducing proteins related to cell survival.

It has also been observed that MMP7 protects cells from cell death by preventing activation of the Fas receptor. This is the first study to show that the Fas receptor undergoes a change in functionality in cells resistant to oxaliplatin, losing the ability to induce apoptosis and promoting pathways linked to cell survival and migration. The authors suggest that, when tumor cells acquire resistance to this drug, continuous exposure could encourage survival of these cells due to an increased expression of MMP7 and the activation of Fas Subsequent studies being carried out by the same group, in collaboration with the Dana Farber Cancer Institute of the Harvard Medical School in Boston, Massachusetts, where Dr. Vanessa Almendro is based, are aimed at explaining the mechanism by which the Fas receptor loses its apoptotic function. Thus, the studies focus on the role played by cholesterol in the cell membrane, as it regulates the functionality of the Fas receptor, preventing it from entering the cell – a key process for this receptor to be able to induce apoptosis.

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