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Conditions in the Tumor Microenvironment Change Role of p53

By BiotechDaily International staff writers
Posted on 09 Aug 2018
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Image: The effects of p53 in cancer-associated fibroblasts on cancer cell migration: Cancer cells (magenta) migrate in the direction of cancer-associated fibroblasts (yellow) that express a non-mutated p53 gene (left); this migration slows down (center) when the p53 in the fibroblasts is silenced; when substances released by the cancer-associated fibroblasts are added to the laboratory dish, the migration is restored (right) (Photo courtesy of the Weizmann Institute of Science).
Image: The effects of p53 in cancer-associated fibroblasts on cancer cell migration: Cancer cells (magenta) migrate in the direction of cancer-associated fibroblasts (yellow) that express a non-mutated p53 gene (left); this migration slows down (center) when the p53 in the fibroblasts is silenced; when substances released by the cancer-associated fibroblasts are added to the laboratory dish, the migration is restored (right) (Photo courtesy of the Weizmann Institute of Science).
Cancer researchers have found that changes occurring in the tumor microenvironment manipulate the activity of fibroblast p53 protein, causing it to promote rather than restrict cancer growth.

Cancer cells coexist with noncancerous adjacent cells that constitute the tumor microenvironment and impact tumor growth through diverse mechanisms. In particular, cancer-associated fibroblasts (CAFs) promote tumor progression in multiple ways. Earlier studies have revealed that in in contrast to the situation in CAFs, p53 in normal fibroblasts (NFs) plays a tumor-suppressive role to restrict tumor growth.

Investigators at the Weizmann Institute of Science (Rehovot, Israel) set out to study the role of p53 in CAFs. To carry out this research, they used a combination of cell culture and a cancer-carrying mouse model.

The investigators reported in the June 19, 2018, issue of the journal Proceedings of the National Academy of Sciences of the United States of America that the transcriptional program supported by p53 was altered substantially in CAFs relative to NFs. In agreement, the secretion of proteins dependent on p53 was also altered in CAFs. This transcriptional rewiring rendered p53 a significant contributor to the distinct intrinsic features of CAFs, as well as promoted tumor cell migration and invasion in culture.

The ability of CAFs to promote tumor growth in mice was greatly compromised by depletion of their endogenous p53. Furthermore, co-cultivation of NFs with cancer cells partially rendered their p53-dependent transcriptome to be more similar to that of CAFs.

The investigators concluded by saying, "Our findings raise the intriguing possibility that tumor progression may entail a nonmutational conversion (“education”) of stromal p53, from tumor suppressive to tumor supportive."

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Weizmann Institute of Science


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