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Email this article On the possible role of incomplete phagocytosis in carcinogenesis and metastasis
Abstract
Chronic inflammation is considered the major contributor to cancer genesis. Chronic inflammation is characterized by: a productive tissue reaction with infiltration by mononuclear cells (macrophages, lymphocytes and plasma cells), foci of necrosis, failure of repair, angiogenesis and tissue sclerosis.
Macrophages are the essential cells involved in chronic inflammation. Chronic inflammation begins with accumulation of a critical number of activated macrophages in one place.
The chronic inflammation can be caused by microbes or non-infectious agents however the body itself is unable to get rid of them. A number of microbes absorbed by macrophages escape destruction. They remain viable and actively multiply. That is a pattern of imperfect phagocytosis. The spread of infection is observed in lymph nodes, liver, lungs and bones. The macrophages that contain microbes become active and begin to secrete inflammatory mediators.
Hypothetically, cancer cells can also cause imperfect phagocytosis and the associated chronic inflammatory reaction. The cancer cells that are trapped in the macrophages may survive due to disruption of apoptosis in them. Imperfect phagocytosis activates macrophages and the above mentioned mechanisms of chronic inflammation.
In the case of imperfect phagocytosis the cancer cells that are hidden in the macrophages can move, penetrate into the lymphatic or blood vessels and easily reach lymph nodes with the aid of macrophages. Cancer cells can multiply inside the carrier macrophages. Having reached the lymph nodes the phagocytes with incubated cancer cells die, then insemination of cancer cells occurs in the lymph nodes and a new cycle starts.
The sizes of microorganisms and stem cells are comparable and vary within 1 - 4 microns. Macrophages are much more active in phagocytizing microobjects 1-4 microns in size. Presumably the small size of stem cancer cells could cause a special macrophage "tropism" to them.
Hidden in the macrophage, cancer cells are partially or completely protected from an immune attack and they become hardly available to chemotherapy as well. Therefore, incomplete phagocytosis can serve as a serious obstacle to successful chemo- or immunotherapy. Presence of dormant or multiple cancer cells in macrophages is predictive signal and indicates the necessity for completion the phagocytosis.
Here we propose the scheme of carcinogenesis:
The violation of apoptosis, immortalization of cancer cells - incomplete phagocytosis - chronic inflammation, remodeling of the extracellular matrix - epithelial mesenchymal transition, anoikis, production of "chimeric" exosomes - transportation of persistent cancer cells by phagocytes – metastasis and tumor progression. Violation of non-specific mechanisms of immunity is the first phase of carcinogenesis, followed by a violation of specific mechanisms - recruitment of T helpers and killers.
Macrophages represent the main “conspirators” in carcinogenesis and the deficiency of phagocytosis is a phenomenon around which the drama of carcinogenesis develops and ignoring this may prevent the goal.
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