A particular genetic polymorphism can apparently decrease one's risk of colon cancer, yet increase risk of breast cancer. How does it work? Sohn et al. undertook to find out exactly what happens at the molecular level to induce this cell-type-specific risk modification. They identified changes in intracellular folate cofactors resulting from the polymorphism that differ between colon and breast cancer cells, providing a possible explanation for the differences in risk.
The mutation in question is a C677T polymorphism of the enzyme methylenetetrahydrofolate reductase, or MTHFR. Epidemiological evidence has mounted, indicating that this variant decreases the risk of several cancers, but increases the risk of others. No molecular evidence has yet provided a possible mechanism for this adjustment of risk, however. In the cell, MTHFR ensures the production of S-adenosylmethionine, or SAM, which is necessary for methylation of cytosine. Using an in vitro model of colon and breast cancer cells, the authors measured the concentrations of SAM and SAH (S-adenosylhomocysteine); they found that both were lessened, and the ratio of SAM to SAH was considerably lower in colon cancer cells expressing the mutant MTHFR than in those expressing the normal enzyme. In breast cancer cells, however, they found higher concentrations of both SAM and SAH in the cells expressing the mutant MTHFR, and the SAM-to-SAH ratio had increased by half. Similarly, the mutation upped homocysteine levels in colon cancer cells and lowered them in breast cancer cells. Overall genomic methylation, the team found, was increased by the mutation in colon cancer cell when the folate supply was high, but decreased when folate was scarce. In breast cancer cells, the mutation decreased genomic methylation when folate was abundant, but had no effect when folate was scarce.
These results mark the first foray into puzzling out the molecular effects of the C677T polymorphism of MTHFR on various cancer cell types and provide the first plausible mechanism for how MTHFR affects risk differently in different cell types.
Compact Spheroid Formation Predicts Invasion
Sodek, et al.. pp. 2060–2070
Ovarian cancer cells can form multicellular spheroid aggregates, a structure that protects the cancer cells from chemotherapeutic agents. But does this spheroid formation also assist in the spread of the cancer? Sodek et al. investigated this question by comparing 6 human ovarian cancer cell lines in their ability to form spheroids and their invasiveness and found a positive relationship between those two characteristics, suggesting that preventing spheroid formation could help beat back ovarian cancer.
Not all ovarian cancers are created equal when it comes to spheroid formation, the authors found: of the 6 cell lines tested, 3 formed compact spheroids, while the others formed loose, sheet-like aggregates that never compacted. The lines that did form spheroids were also able to invade 3-D collagen matrices, while the others failed to do so, pointing to a correlation between invasiveness and spheroid formation. The spheroid-forming lines also showed the ability to contract a collagen gel, a more spindle-like morphology, and upregulation of several key genes characteristic of TGF-beta-mediated fibrotic response. The results of this study suggest that attacking the contractile behavior that promotes spheroid formation and matrix invasion could effectively help thwart ovarian cancer.
The Prognostic Power of Claudin-4
Lanigan, et al., pp. 2088–2097
As breast cancer progresses, cells become disorganized, and the junctions between cells become altered. Lanigan et al. investigated the distribution and potential clinical value of one of the proteins involved in cell-cell adhesion. They found that the protein, claudin-4, independently predicted survival in the entire cohort of breast cancer patients.
The family of proteins known as claudins are considered to be the backbone of tight junctions between cells, and several members of the family are overexpressed in a variety of cancers. Previous studies of claudin-4 have produced contradictory results, and no previous study has linked claudin-4 expression with survival. In this study, the authors examined claudin-4 expression in clinical samples of normal and breast tumor tissues. They found that the tumors exhibited increased claudin-4 expression compared with the normal tissue, that higher grade tumors expressed more claudin-4 than those of lower grade, and that estrogen receptor (ER)-negative tumors expressed more than ER-positive ones. Then, in a larger cohort of 299 tumor samples, the authors correlated claudin-4 expression with survival and concluded that higher levels of claudin-4 spell bad news for the patient. Even after eliminating the ER-negative tumors, which typically carry a poor prognosis anyway, higher claudin-4 expression corresponded with a lackluster response to tamoxifen and reduced survival.
This study marks the first time anyone has linked claudin-4 with tamoxifen response. Although the mechanism by which claudin-4 relates to prognosis is not yet evident, it may turn out to be a useful breast cancer biomarker.