Pericytes, a type of little-studied peripheral cell found in small blood vessels, may serve an important function in containing cancer metastasis. As experiments have shown, the results of which are published in the journal Cancer Cell,

Modern chemotherapy, which suppresses the growth of blood vessels and reduces the number of pericytes in the tumor, can have the opposite effect, making cancer cells more aggressive and prone to metastasis.

Angiogenesis, or the process of formation of new blood vessels in growing cellular tissue, is currently considered one of the most effective targets in clinical therapy for certain types of cancer, such as breast cancer. Since intensive vascular formation is one of the key factors for the rapid growth of tumors,

The search continues for more and more advanced drugs that suppress the growth of blood vessels that supply cancer cells with nutrients and oxygen, without which malignant cells degrade.

Focusing on pericytes, specific cells involved in the formation of the walls of small blood vessels, a team of researchers led by Harvard Medical School professor Raghu Kalluri decided to find out whether it was possible to selectively “turn off” these cells to achieve the same effect of tumor degradation as when use of drugs that inhibit angiogenesis. Further, if the result is positive, chemotherapy that inhibits vascular growth could be improved by making it more targeted.

It was possible, as usual, to see whether pericytes are the Achilles heel of cancer, using mutant mice.

First, genetically modified animals were bred that were sensitive to the action of a drug that suppressed these cells. Then, after introducing this drug into implanted mammary tumors, the number of pericytes in malignant tissues was reduced by up to 40%. At first, the results seemed encouraging: after 25 days, tumors with a reduced content of pericytes had decreased in size by a third. But, as it turned out, there was nothing to rejoice at: contrary to the well-established point of view in oncology that inhibition of angiogenesis effectively suppresses cancer, it was found that

In mutant mice, the number of secondary tumors in the lungs was three times higher than the number of secondary tumors observed in normal mice in the control group.

In other words, there was a strong correlation between decreased pericyte numbers and more aggressive metastases.

Not stopping there, Kalluri's group decided to figure out the mechanism behind this by doing a detailed molecular analysis of cancer tissues with a reduced content of pericytes.

As one would expect, the size of areas suffering from a lack of oxygen in tumors with a low content of pericytes turned out to be five times larger than in normal ones: without pericytes, whose numerous special processes, covering the walls of blood vessels, form a bed for further growth of the endothelium (the most important first layer that forms the inner wall of the vessel), the vascular network of the tumor weakens, becomes more sparse and is no longer able to supply cancer cells with oxygen.

Due to the resulting hypoxia, the cells die and the tumor shrinks.

It seems that the goal has been achieved, but why is tumor shrinkage accompanied by increased metastases according to the principle “we treat one thing and cripple another”?

As the authors of the article in Cancer Cell found out, a protective reaction to suffocation is the reverse reprogramming of cancer cells from differentiated epithelial cells (epithelium forms most of the body's glands, including the mammary glands) into mesenchyme - cells of embryonic connective tissue that have greater mobility and, similar to stem cells, greater survivability. Evidence of this transformation was a fivefold higher content of the EMT marker, a specific protein that marks epithelial-mesenchymal transformation. In addition, tumors with a reduced content of pericytes also contained five times more Met receptor molecules that regulate cell motility and growth.

It is also interesting that the smaller the tumor in the mutant mouse, the more pronounced the EMT and Met markers were, indicating the “rejuvenation” of cancer cells and an increase in their mobility. Accordingly, pulmonary metastases in such “cured” mice were more frequent and severe.

Thus,

developed large tumors with a normal content of pericytes were, paradoxically, less prone to metastasis than undeveloped tumors of the same type with suppressed pericytes.

However, the authors did not stop there, testing Imatinib and Sunitinib, clinical oncological drugs that suppress angiogenesis, on mice. Both caused a 70 percent reduction in the number of pericytes in the mice's cancerous tissues, but the number of secondary tumors also tripled. A similar relationship was found when repeating the same experiments on other types of cancer - renal carcinoma and melanoma, and also when comparing the data obtained with the results of an analysis of 130 samples of human tumors,

confirming the same relationship between reduced pericytes and high Met expression, on the one hand, and more developed metastases, as well as a lower survival rate of patients in the next 5 and 10 years after treatment with drugs that suppress angiogenesis, on the other.

As the authors summarize, the results obtained should cause a significant revision of some established dogmas of clinical oncology and adjust the common cancer therapy based on the inhibition of angiogenesis in tumors. Thus, additional experiments on mice showed that a combination of pericyte-inhibiting drugs with Met-inhibiting drugs helps suppress the EMT transformation of cancer cells and subsequent metastases.

Some cells inside advanced tumors can suppress metastases