Researchers here report on work that identifies SOX17 inhibition as a potential way to attack colon cancer in its early stages. Any successful cancer must have adopted one or more ways to suppress the immune system in order to grow past the earliest stages of a few cancerous cells. Interfering in those suppression mechanisms is a potential basis for therapy, as the researchers demonstrated here. Whether or not this line of work will make much further depends on whether an economically viable approach to SOX17 inhibition can be found, and whether or not it is a good target for many other forms of cancer.
Colon cancer usually arises in long-lived cells called intestinal stem cells, whose job is to continually regenerate the lining of the intestines. To learn more about how these precancerous growths evade the immune system, the researchers used a technique they had previously developed for growing mini colon tumors in a lab dish and then implanting them into mice. In this case, the researchers engineered the tumors to express mutated versions of cancer-linked genes Kras, p53, and APC, which are often found in human colon cancers.
Once these tumors were implanted in mice, the researchers observed a dramatic increase in the tumors' expression of SOX17. This gene encodes a transcription factor that is normally active only during embryonic development, when it helps to control development of the intestines and the formation of blood vessels. The researchers' experiments revealed that when SOX17 is turned on in cancer cells, it helps the cells to create an immunosuppressive environment. Among its effects, SOX17 prevents cells from synthesizing the receptor that normally detects interferon gamma/en.wikipedia.org/wiki/Interferon_gamma">interferon gamma, a molecule that is one of the immune system's primary weapons against cancer cells.
Without those interferon gamma receptors, cancerous and precancerous cells can simply ignore messages from the immune system, which would normally direct them to undergo programmed cell death. Without interferon gamma signaling, cancer cells also minimize their production of molecules called MHC proteins, which are responsible for displaying cancerous antigens to the immune system. The cells' insensitivity to interferon gamma also prevents them from producing immune molecules called chemokines, which normally recruit T cells that would help destroy the cancerous cells.
When the researchers generated colon tumor organoids with SOX17 knocked out, and implanted those into mice, the immune system was able to attack those tumors much more effectively. This suggests that preventing cancer cells from turning off SOX17 could offer a way to treat colon cancer in its earliest stages. As part of their study, the researchers also analyzed gene expression data from patients with colon cancer and found that SOX17 tended to be highly expressed in early-stage colon cancers but dropped off as the tumors became more invasive and metastatic.
Link: https://news.mit.edu...une-system-0228
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