Inactivation of p53 allows cancer cells to acquire stem cell properties

p53 is an important tumor suppressor gene in humans. The biological function of normal p53 is like a "Guardian of the Genome". In the G1 phase, DNA damage points are checked to monitor the integrity of the genome. When the genome is damaged, the p53 protein prevents DNA replication to provide enough time for the damaged DNA to repair; if the repair fails, the p53 protein will cause apoptosis. When both copies of the p53 gene are mutated, the proliferation of the cell will be out of control, causing the cell to become cancerous.

Researchers from the Sack Institute for Biological Research and the Advanced Research Institute of Princeton University have recently discovered that p53 can also inhibit the transformation of cancer cells into a more aggressive stem cell-like state. Based on this new feature of p53, the researchers called it "Guardian against Genome Reprogramming". The research paper was published in PNAS magazine this week.

"It is well known that poor differentiation, cellular and genetic heterogeneity are important characteristics of many invasive and lethal cancers," said Professor Wahl of the Gene Expression Laboratory of the Sark Institute for Biological Research. Cancer cells. Our findings indicate that p53 mutations can regenerate tumor cells to regain stem cell-like 'programming.' "

"Cancer cells need to acquire certain characteristics of stem cells such as immortality to survive and adapt to the changing environment. Immortality enables cells to constantly renew themselves and generate progenitor cells that can differentiate into other cell types," Wahl said: The tumors are all different cell aggregates composed of cancer cells, but at present we still cannot understand the mechanism of tumor heterogeneity. "

In the past, scientists attributed the cellular diversity of tumors to their genetic instability. As the tumor cell population expands, individual cells undergo random mutations, and the molecular characteristics of the cells begin to differ. Eventually, millions of different cancer cells make up the tumor.

In addition, some scientists also believe that the heterogeneity of tumors is caused by the de-differentiation of fully stereotyped and specialized cells in the process of tumor development and development. However, this theory was eventually discarded and replaced by the current popular cancer stem cell theory. Cancer stem cell theory holds that there is an important class of cells in cancer, namely cancer stem cells. These cancer stem cells may originate from normal stem cells or early progenitor cells. Unlike other tumor cells, they have the ability to renew themselves and can generate non-stem cells like normal stem cells.

"Our research results show that cancer cells similar to stem cells are not part of early tumors, but only appear with the loss of p53 function in the late stage of tumor development," Benjamin T. Spike, co-author of the paper and postdoctoral researcher Say: "Tumor heterogeneity may be due to a combination of increasing genomic instability and epigenetic instability associated with stem cell-like phenotypes."

In the new study, the researchers confirmed that p53 not only functions as a "genomic guardian", but this tumor suppressor is also an important obstacle to blocking somatic cell reprogramming.

In order to determine the effect of p53 inactivation on the appearance of stem cell-like cancer cells, Spike and Mizuno screened hundreds of gene expression profiles in breast and lung cancer closely, looking for stem cell-like markers and detecting their association with p53 status . "We found that p53-mutated or inactivated tumors are closely related to stem cells in gene expression patterns," Spike said. "The loss of p53 allows cells to overcome death and proliferation barriers and become tumorigenic."

Wahl hopes to have a deeper understanding of the process by which tumor cells transform into a stem cell-like state in the next study. "The closer tumors are to stem cells, the more aggressive they are, but they still have the ability to differentiate into less aggressive cell types," Wahlshuo said: "If we can use this potential, we may be able to force these cells to redifferentiate, Thereby reducing their danger.

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