Many laboratories around the country have been paying attention to understanding how cancer develops. This implies gaining knowledge about how such cells migrate from the primary tumour to distant sites in the body and also about developing therapies to inhibit this process.
Cell Migration and Metastasis
Researchers at the Medical University of South Carolina (MUSC) identified a mechanism that can help in regulating signalling events leading to cell migration and metastasis. They also showed in the Oct, 2017 issue of Science Signalling, that primary cilia act as a focal point to transmit growth signals. Moreover, they identified a specific ceramide species that disrupts the cell’s ability to form this focal point.
According to Besim Ogretmen, Ph.D., senior author of the study, director of the Developmental Cancer Therapeutics Programmes at the Hollings Cancer Center and professor of Biochemistry and Molecular Biology at MUSC, this could be one way by which cancer cells could actually migrate from one place to another to induce metastasis leading to metastatic cancer.
The Ogretmen laboratory studies the signaling lipid ceramide and its role in many biological pathways, including cancer biology. Family of six ceramide synthase enzymes help information of ceramides in the cells. In order to identify how these various enzymes function, the laboratory-generated mice that lacked each of these enzymes. Mice lacking CerS4 suffered from a condition in which the hair got lost from some or all parts of the body known as alopecia.
What the Current Studies Show
Keratinocytes, or skin cells, migrate through the outer skin to maintain hair follicles. In the absence of CerS4, these keratinocytes become hyperactive and migrate too much, thereby disrupting the hair cycle. Ogretmen points out that this phenotype was unexpected, the increased migration observed in these keratinocytes might also occur in the cancer cells. This case hair loss reflected unexpected phenotypes through animal models and something very significant in cancer biology like things about cancer metastasis and how it could be regulated.
The findings from the laboratory showed that ceramide affected cell migration, which is tightly controlled. When the cytokine transforming growth factor beta also known as TGF-beta gets sensed by the TGF-beta receptor, the receptor gets concentrated within the primary cilia of the cells. The cell then changes the proteins it makes to allow the cell to migrate. Ceramide produced by CerS4 binds to Smad7, a cellular protein that can bind the TGF-beta receptor. The binding of ceramide to Smad7 prevents the TGF-beta receptor from concentrating in the cilia. As a result, ceramide prevents the cell from making proteins needed for migration.
After identifying a signalling pathway in the cells, at the next step, researchers wanted to determine if this pathway was significant in cancer patients. Ogretmen laboratory screened previously reported microarray data sets of several human tumour tissues and showed that, only the levels of CerS4 were significantly decreased in these samples. Using preclinical models, they showed that tumour cells that lost CerS4 expression had an increased incidence of metastasis to distant organs. This increased metastasis could be mitigated when the cell made more Smad7, which inhibited the TGF-beta receptor. This report suggests that only the ceramide generated from CerS4 regulates migration that is mediated by the TGF-beta receptor.
Future Researches and Studies
Future studies would look at developing a better model to study tumour development and metastasis in the context of CerS4. The laboratory plans to better define the way in which CerS4 regulates cell migration and metastasis by decreasing the CerS4 in the mice. These mice would provide a model to test new therapies aimed at preventing metastasis.
Like every approach, this approach also has some limitations. For instance, targeting the TGF-beta receptor could have detrimental effects on other tissues of the body. It might also result in Bardet-Biedl syndrome which is a metabolic disease in which trafficking of proteins within the cilium gets blocked. As a result, targeting the formation of the cilium could prove to be difficult.
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