Indeed, CSCs for non-hematopoietic

cancer are probed by heterotopic xenotransplantation of limiting numbers of putative CSCs in immunocompromised mice, outside of a niche. Tumorigenicity in immunocompromised mice (the mainstay of any demonstration of CSCs) coincides with the ability of a cancer subclone (a metastatic subclone) to grow efficiently outside of their original microenvironment, independent of it, or in a different microenvironment. For this reason, one might argue (against the flow of a portion of the current literature) that demonstration of a CSC in most instances coincides with demonstration of the dispensability of the primary niche. There is, conversely, little doubt of the fact that most hematopoietic Selleckchem EPZ6438 cancers grow primarily in the bone/bone marrow organ, and some types of both hematopoietic (lymphoma) and non-hematopoietic cancer have an exquisite tropism for bone as a secondary site. The specific role for bone marrow stromal progenitors www.selleckchem.com/products/ABT-888.html in supporting the growth of hematopoietic cancer can be as diverse as the variety of hematopoietic cancers themselves, and can directly reflect on the pattern of their growth and the type of local organ damage they can produce.

In multiple myeloma, for example, the CXCL12/CXCR4 axis, which is thought to operate in the recruitment of a variety of blood borne cells including circulating cells from epithelial cancer and normal HSCs, can account for both the recruitment of myeloma cells to bone marrow and the promotion of their local survival [61] and [62]. Myeloma cells are thought to represent post-germinal center B cells with somatic hypermutation and a phenotype consistent with

memory B cells [63], which in a way makes myeloma a unique kind of “metastatic-only” cancer that involves selectively the bone marrow but may not arise within it. The unique ability of myeloma to produce lytic lesions in bone, on the other hand, can in turn be traced to different mechanisms, in turn centered on the interaction of myeloma cells with stromal osteoprogenitors. Dickkopf-1 Etomidate (DKK-1), a Wnt antagonist, is involved in inhibition of the osteogenic potential of stromal osteoprogenitors, while RANKL overexpression and downregulation of osteoprotegerin in stromal cells are intuitively linked to promotion of bone resorption culminating in the production of osteolytic lesions [64]. A number of additional mechanisms can, however, contribute to this effect, including the generation of Th17 cells, immune inhibition of clonal growth in the pre-myelomatous monoclonal gammopathies of undefined significance (MGUS), and modulation of macrophage and dendritic cell function.