Abstract
Subendothelial cells (pericytes) are the clonogenic, multipotent and self-renewing skeletal stem cells (SSCs) found in bone marrow (BM) stroma. They express genes maintaining hematopoietic stem cell (HMC) niche identity and, transplanted in immunocompromised mice, organize the hematopoietic microenvironment (HME) generating humanized bone/BM ossicles. To create a mouse model of hematogenous metastasis of human prostate cancer (PC) cells to human bone/BM, we injected PC cells in the blood circulatory system of Severe Combined Immunodeficiency (SCID)/beige mice bearing heterotopic ossicles. Results indicate that PC cells could efficiently home to mice-implanted extraskeletal BM ossicles, but were not able to colonize mice skeletal segments. In humanized bone/BM ossicles, early foci of PC cells occupied a perisinusoidal position, in close contact with perivascular stromal cells. These findings demonstrate the importance of the SSC compartment in recreating a suitable environment to metastatic PC cells. Our data support the hypothesis that BM SSCs committed to a pericyte fate can specify for homing niches of PC cells, suggesting an involvement of specific interactions with subendothelial stromal cells in extravasation of circulating metastatic PC cells to BM.
Highlights
Bone is a privileged metastatic site for numerous tumors and the most common for prostate cancer (PC) [1]
Identical experiments were conducted in Severe Combined Immunodeficiency (SCID)/beige mice where extraskeletal bone/bone marrow (BM) ossicles were generated by transplanting human BM skeletal stem cells (SSCs) cultured in vitro to form cartilage pellets (Figure 2C)
The same cell type has the property of establishing a hematopoietic microenvironment for circulating hematopoietic progenitors, and is itself a skeletal progenitor/stem cell [7,11]
Summary
Bone is a privileged metastatic site for numerous tumors and the most common for prostate cancer (PC) [1]. Recent reports have shown that BM specialized vascular structures delineate a microenvironment supporting metastasis of leukemia cells Cancers 2019, 11, 763 around capillaries and pericytes topically overlap with hematopoietic progenitor cell niche [4] and are characterized by C-X-C motif chemokine 12 (CXCL12) expression [5], whose receptor CXCR4 is frequently overexpressed on primary tumor cells [6]. These areas have been characterized for homing of leukemia cells [6], but they are probably important for metastasis of circulating solid cancer cells.
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