"Stem" model of carcinogenesis

Studies of the last 50 years have made it possible to characterize the work of mechanisms regulating the behavior of normal stem cells and their descendants. Special attention was drawn to the property of stem cells to self-renewal, which provided stem cells with an unlimited lifetime and proliferation. Their direct descendants (ancestral cells) retained some ability to self-renew during proliferation, but the presence of an internal mechanism for accounting for cell divisions limited their lifespan. As the differentiation process progressed, the ability to reproduce these descendants of primary cells steadily declined, and they could undergo an ever-decreasing number of cell divisions. The most illustrative example of such a system is the formation of shaped elements of the blood and immune system.

But stem cells divide and differentiate under strict control. Without such a regulatory mechanism, their behavior will not differ much from the reproduction of cancer cells, and as knowledge about the features of stem cells and the characteristics of cancer cells accumulates, many researchers have found an obvious parallel between them. This concerned, first of all, unlimited lifespan, the ability to give rise to cells of other types and migrate to different parts of the body.

The previously existing idea that all cancer cells have the same proliferative potential and are equally responsible for the development of cancer has been shaken. To date, it has become clear that in many types of cancer, such properties are inherent in only a small part of the tumor cells. The common features of stem and cancer cells allowed us to call malignant ancestral cells cancer stem cells. These cells appear to be the result of a malfunction in the regulatory system of damaged stem cells or their direct descendants.

It should be noted that the hypothesis of the existence of a small population of cancer stem cells that trigger the oncological process is not new. Back in the early 60s of the last century, data began to appear that groups of cells of the same tumor differ in their ability to give rise to new tumors. Significant differences were also found in the ability to proliferate tumor cells in in vitro culture. It became possible to isolate and study different cell populations of the same tumor later. This was due to the development of new research methods. In the 1970s, a method of flow cytometry was invented, which made it possible to automatically sort cells based on the presence of unique markers on their surface. In the 1990s, a test was developed for the ability of cell populations to self-renew, after which it became possible to ensure the growth of normal human stem cells in the body of mice. Using these techniques, John E. Dick (University of Toronto) in 1994 began to identify cancer stem cells in leukemia and proved their presence for the first time, and Richard Jones (Johns Hopkins University) in 2003 identified a population of cancer stem cells in patients with multiple myeloma. In the same year, a group of researchers from the University of Michigan published the first data on the presence of cancer stem cells in solid tumors. In 2004, Peter Dirks (University of Toronto) identified similar cells in primary tumors of the human nervous system. To date, cancer stem cells that give rise to malignant neoplasms have been uniquely identified in patients suffering from acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, multiple myeloma, brain tumors, prostate cancer. These cells are capable of self-renewal and regeneration of all types of cells that make up the original tumor. A limited number of cancer stem cells can give rise to the tumor process, constantly maintain the population of tumor cells and regenerate it after the removal or destruction of most of its cells.

The behavior of normal stem cells is under strict genetic control and is implemented in accordance with the signals they receive from the immediate environment (niche). The occurrence of mutations in stem cells, their inheritance by ancestral cells, as well as the perversion of the response of stem cells to external signals can lead to the transformation of healthy stem cells into cancer cells.

Thus, recent studies have shown that only a small population of tumor cells is responsible for the development of the pathological cancer process. If this population of cells remains in the body when the tumor is removed, then the resumption of the malignant process cannot be avoided. But when it is destroyed, the remaining tumor cells will die by themselves, having exhausted their proliferative potential. Therefore, cancer stem cells are the main target for antitumor drugs, but for this, first of all, it is necessary to learn how to detect and isolate them, since they cannot be identified solely by their appearance.