How do metastases form from primary tumors? For cells within a primary tumor to become metastatic multiple events must occur and failure of any one step will prevent metastasis. Tumor cells must detach from the primary tumor mass, increase their motility (movement), enter into the circulation, survive transport within the circulation, exit the circulation, and successfully colonize a new tissue. (1) Metastasis is highly inefficient; millions of tumor cells might enter the bloodstream every day, but only a small fraction ever succeed in successfully colonizing another tissue. This suggests healthy tissues are very hostile to invading cells, and tumor cells must overcome multiple barriers in order to successfully metastasize.(2)
Cells within a tumor are highly heterogeneous, meaning that they contain many genetically distinct types of cells, each of which arise through random mutations. Each type of cell has a different metastatic potential. Studies of individual metastases suggest each metastasis is descends from a single tumor cell.(3) Researchers originally believed mutations resulting in metastastic ability develop late in the life of the primary tumor. However, new evidence suggests metastatic cells are a component of early malignant tumors, as cells expressing genes required for metastasis can be isolated from early tumors. In addition, early stage cancer patients often have micrometastases (very small metastases that have not yet developed into tumors).(4)
The video below, from the Winship Cancer Institute of Emory University, shows how current research is attempting to identify the ‘leader’ and ‘follower’ cancer cells responsible for the invasion and spread of cancer.
Recent work has suggested that stem cells from the bone marrow are recruited via the circulation to colonize and condition the niche even before any cells have left the original tumor. This recruitment appears to be in response to factors (primarilyVEGF) released by the primary tumor, although the mechanisms involved are unclear(5). Other work has demonstrated that release of factors (VEGF, TGF-a, and TNF-b) from the primary tumor results in expression in the lung of molecules(chemoattractants) that lure tumor cells to the lung(6). Breast cancers often metastasize to bone. A specific molecule in normal and cancerous mammary epithelial cells allows them to interact with cells present in the bone and is the cause of this specific spread(7).