On the trail of malignant manipulations: Certain cancer mutations not only promote the growth of the tumor cells themselves, but can also cause the surrounding tissue to promote disease, a study shows. In a mouse model, the researchers were able to show that breast cancer cells with a widespread mutation manipulate nearby fat cells so that they inhibit the body’s own immune response against the tumor and thus promote its growth. The scientists say that there could be potential for cancer medicine in influencing this process.
They are also called “degenerate”: cells with certain damage to their genetic material can proliferate uncontrollably – there is a risk of life-threatening cancer. Various genes are already known that, when mutated, lead to the formation of tumor cells. Programs that control cellular development processes can be disrupted, which leads to the development of malignant potential. However, tumor cells can also have mutations in certain genes that lead to the inhibition of mechanisms that counteract the development and progression of cancer. This category also includes the particularly common mutations in the gene called p53. In around 30 percent of all cases of breast cancer, the cancer cells have errors or complete loss of function in this genetic makeup.
A defective “cancer brake” in sight
Previous studies have already explored the effects of p53 mutations in the cancer cells themselves. It became clear that the “healthy” gene is associated with the suppression of cancer development processes. There were also indications that p53 mutations in cancer cells could also affect cells in the tumor microenvironment, thereby further driving cancer growth. An Israeli-German research team led by Ori Hassin from the Weizmann Institute of Science in Rehovot has now followed this lead experimentally. Using the mouse model of breast cancer, the scientists examined the extent to which cancer cells with p53 mutations affect the characteristics of fat cells. These so-called adipocytes are the typical neighbors of the tumors in the breast tissue.
For their study, the scientists first treated laboratory cultures of adipocytes with culture medium in which breast cancer cells with or without p53 mutations had previously grown. As they report, the subsequent investigations showed clear differences: Apparently the p53 cancer cells had released something into their culture medium that had a particularly strong effect on the fat cells. The team found more intensive changes in metabolism and gene activity in the adipocytes compared to the control, as well as increased production of inflammatory messenger substances. In addition, the maturation of the cells was inhibited and fat cells that had already developed were returned to an immature state.
Reprogrammed fat cells protect the tumor
In the next step, the researchers transferred breast cancer cells with a mutated or functional p53 gene together with fat cells to healthy mice and carried out comparative studies on the newly formed tumors. They discovered that if p53 was mutated in the cancer cells, a particularly large number of immune cells migrated into the tumor tissue and mitigated the defense reactions. They had features on their surface that are known to be potent brakes on the immune defense against cancer cells. It is now clear: p53-mutant breast cancer cells reprogram nearby fat cells so that they create an inflammatory microenvironment that inhibits an immune response against the tumor, the researchers conclude.
According to them, the study result is now an important starting point for further research: “Elucidating the interaction between p53 and adipocytes in the tumor microenvironment could offer effective therapeutic targets for the treatment of breast cancer patients,” write the scientists. Co-senior author Almut Schulze from the German Cancer Research Center in Heidelberg concludes: “Fat cells are a very important component of breast tissue and can therefore have a massive influence on tumor development. Further research could therefore provide new clues as to how the progression of breast cancer can be stopped,” said the scientist.
Source: German Cancer Research Center, specialist article: PNAS, doi: 10.1073/pnas.2311460120