Metastasis is the spread of cancer cells from their original site of origin in the primary tumor to distant tissues and organs. About 80% of tumors originate in the epithelial linings of the skin and various invaginations in the body such as the airways, milk ducts, and GI tract. Most of these are carcinomas (e.g., lung, breast, colon) and melanomas (melanocytes).
It is thought that the primary tumor develops from a single cell that has collected enough mutations to get its mitotic cycle stuck in the “on” position. Deregulated cell division results in a tumor consisting of ancestors from the original mutated cell. If cells continue to divide at a faster rate than they die, the tumor gets larger. But what causes some of these cells to metastasize, i.e., to gain the ability to leave their site of origin in the epithelium, migrate into the mesoderm, and disseminate throughout the body?
It is abundantly clear that metastasis is what makes cancer so deadly. If we just had to manage the primary tumor and not the spread, cancer survival would soar. The primary tumor can be surgically removed, the local area can be treated by radiation, and the patient can receive preventive chemotherapy. If spread hasn’t occurred, there is usually an excellent outcome. But once a cancer cell enters the vasculature or lymphatics and disseminates throughout the body, all the while continuing to divide, treatment is far more problematic.
Not only do the metastatic cancer cells migrate to virtually anywhere (lungs, brain, bone marrow, liver) but they are usually devilishly resistant to chemotherapy and radiation. Treatments to combat metastases often become palliative and no longer curative. Mortality occurs when vital organs fail due to tumor burden.
It is therefore surprising that so little is known about the onset of metastasis. While many of the molecules in the actual mechanics of metastasis are known, how it all gets started is still a mystery.
To my knowledge, the century-old theory of cancer cell fusion with tumor-associated leucocytes such as macrophages is really the only complete theory we have—potentially explaining most, if not all, aspects of metastasis and particularly its initiation
In this theory, metastasis is virtually a second disease imposed on the primary tumor cell. While the primary cell is notable for its deregulated cell cycle, it has little propensity to migrate away from its site of origin.
The fusion theory states that acquisition of a metastatic phenotype occurs when a healthy migratory leucocyte such as a macrophage fuses with a primary tumor cell. The resultant hybrid is a migratory cell with the uncontrolled cell division of the original cancer cell. A metastatic cell emerges, which, like a white blood cell, can migrate from the epithelium into the mesoderm, enter the circulatory system and travel to lymph nodes and distant organs.