A Transformative Approach to Cancer Metastasis: Primo Vascular System as a Novel Microenvironment for Cancer Stem Cells

Metastasis is the principal cause of death among cancer patients. Despite intensive research with the application of genetic and molecular biology, its prevention and management remain far from satisfactory. More innovative approaches are needed. The major routes for tumor dissemination are the two circulatory systems, lymphatic vessels and blood vessels, so the metastases occurring through them are referred to as lymphatic and hematogenous metastases, respectively. Surprisingly, a new circulatory system, named the primo vascular system (PVS), which is composed of very thin primo vessels (PVs) and primo nodes (PNs), has recently emerged as a third circulatory system. Thus, a natural conjecture would be that the PVS might be associated with carcinogenesis and metastasis, and, indeed, that conjecture has been supported by strong evidence of metastasis in rodents with xenograft tumors. In fact, a study showed that migration of tumor cells to secondary sites was more efficient in the PVS than in the lymphatic system. In addition, the PVS is also a conduit for a fluid, which, according to proteomic analyses contains remarkably high levels of carbohydrate metabolic derivatives that are usually associated with stem cells, cancer cells and differentiated myeloid cells. Thus, the PVS has the potential to transport growth and communication factors between primary and secondary tumor sites, thereby enhancing the oncogenicity of tumor cells at secondary sites. Furthermore, the study of a tumor-derived PVS in murine xenografts of human histiocytic lymphoma has suggested that the PVS may provide a safe haven for a select population of cancer stem cells. These pieces of evidences for the involvement of the PVS in cancer metastasis is call for more intensive investigations of its possible role as an incubating microenvironment for tumor formation, propagation, sustenance, and relapse.