HSC homing, quiescence, and self-renewal depend on the bone marrow HSC niche. A large proportion of solid tumor metastases are bone metastases, known to usurp HSC homing pathways to establish footholds in the bone marrow. However, it is not clear whether tumors target the HSC niche during metastasis. Here we have shown in a mouse model of metastasis that human prostate cancer (PCa) cells directly compete with HSCs for occupancy of the mouse HSC niche. Importantly, increasing the niche size promoted metastasis, whereas decreasing the niche size compromised dissemination. Furthermore, disseminated PCa cells could be mobilized out of the niche and back into the circulation using HSC mobilization protocols. Finally, once in the niche, tumor cells reduced HSC numbers by driving their terminal differentiation. These data provide what we believe to be the first evidence that the HSC niche serves as a direct target for PCa during dissemination and plays a central role in bone metastases. Our work may lead to better understanding of the molecular events involved in bone metastases and new therapeutic avenues for an incurable disease. IntroductionMetastases represent the most common malignant tumors involving the skeleton: nearly 70% of patients with breast cancer or prostate cancer (PCa) -and approximately 15%-30% of patients with carcinomas of the lung, colon, stomach, bladder, uterus, rectum, thyroid, or kidney -have bone lesions (1). Several mechanisms are thought to account for the organ-specific nature of bone metastases, including direct tumor extensions, retrograde venous flow, and tumor embolization. It is also clear, however, that anatomy alone does not explain the organ-specific pattern of metastasis.One hypothesis that has gained favor is that the metastatic process is functionally similar to the homing behavior of HSCs to the BM (2, 3). HSC homing, quiescence, and self-renewal in the BM are now known to depend on a region termed the HSC niche (4, 5). Recent studies identified cells of the osteoblastic and endothelial lineages as key components of the niche (6-11). Molecules that play critical roles in HSC niche selection are now thought to be used by metastases to establish footholds in the BM (2, 3), including chemoattractants (CXCL12; also referred to as stromal-derived factor-1; refs. 3, 12), attachment factors (annexin II [Anxa2]; ref. 13), regulators of cell growth, and vascular recruitment ref. 14). Once in the BM, tumor cells parasitize the bone microenvironment to regulate long-term survival/dormancy and, ultimately, metastatic growth. However, it is not known whether metastatic cells specifically target the HSC niche during dissemination.In the present work, we used a PCa model to demonstrate that tumors directly compete with HSCs for occupancy of the endosteal HSC niche during BM transplantation (BMT). Critically, HSCs

In 973 consecutive patients with an incidental adrenal mass and no history of cancer, no malignant lesions were identified. Adenomas (75%) and myelolipomas (6%) were the most common lesions.

BackgroundIt is well established that bleeding activates the hematopoietic system to regenerate the loss of mature blood elements. We have shown that hematopoietic stem cells (HSCs) isolated from animals challenged with an acute bleed regulate osteoblast differentiation from marrow stromal cells. This suggests that HSCs participate in bone formation where the molecular basis for this activity is the production of BMP2 and BMP6 by HSCs. Yet, what stimulates HSCs to produce BMPs is unclear.Methodology/Principal FindingsIn this study, we demonstrate that erythropoietin (Epo) activates Jak-Stat signaling pathways in HSCs which leads to the production of BMPs. Critically, Epo also directly activates mesenchymal cells to form osteoblasts in vitro, which in vivo leads to bone formation. Importantly, Epo first activates osteoclastogenesis which is later followed by osteoblastogenesis that is induced by either Epo directly or the expression of BMPs by HSCs to form bone.Conclusions/SignificanceThese data for the first time demonstrate that Epo regulates the formation of bone by both direct and indirect pathways, and further demonstrates the exquisite coupling between hematopoesis and osteopoiesis in the marrow.

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Crosstalk between hematopoietic stem cells (HSCs) and the cells comprising the niche is critical for maintaining stem cell activities. Yet little evidence supports the concept that HSCs regulate development of the niche. Here, the ability of HSCs to directly regulate endosteal development was examined. Marrow was isolated 48 hours after "stressing" mice with a single acute bleed or from control nonstressed animals. "Stressed" and "nonstressed" HSCs were cocultured with bone marrow stromal cells to map mesenchymal fate. The data suggest that HSCs are able to guide mesenchymal differentiation toward the osteoblastic lineage under basal conditions. HSCs isolated from animals subjected to an acute stress were significantly better at inducing osteoblastic differentiation in vitro and in vivo than those from control animals. Importantly, HSC-derived bone morphogenic protein 2 (BMP-2) and BMP-6 were responsible for these activities. Furthermore, significant differences in the ability of HSCs to generate a BMP response following stress were noted in aged and in osteoporotic animals. Together these data suggest a coupling between HSC functions and bone turnover as in aging and in osteoporosis. For the first time, these results demonstrate that HSCs do not rest passively in their niche. Instead, they directly participate in bone formation and niche activities.

CT virtual cystoscopy is a promising technique for use in bladder tumor detection of lesions larger than 5 mm. Optimal evaluation requires adequate bladder distention with the patient in both supine and prone positions and interpretation of both transverse and virtual images.

Differentiation of hematopoietic stem cells (HSCs) after birth is largely restricted to the bone marrow cavity, where HSCs are associated closely with osteoblasts (OBs). How OBs localize HSCs to the endosteal niche remains unclear. To explore adhesive interactions between HSCs and OBs, a cell blot analysis was used that revealed 2 major bands that corresponded to monomers and multimers of annexin II (Anxa2). Immunohistochemistry revealed that OBs and marrow endothelial cells express Anxa2 at high levels. Function-blocking studies confirmed that Anxa2 mediates HSC adhesion mainly via the N-terminal portion of the Anxa2 peptide. Adhesion of HSCs to OBs derived from Anxa2-deficient animals (Anxa2−/−) was significantly impaired compared with OBs obtained from wild-type animals (Anxa2+/+). Moreover, fewer HSCs were found in the marrow of Anxa2−/− versus Anxa2+/+ animals. Short-term lodging, engraftment, and survival of irradiated mice with whole marrow cells were substantially inhibited by N-terminal peptide fragments of Anxa2 or anti-Anxa2 antibodies. Similar findings were noted in long-term competitive repopulation studies. Collectively, these findings reveal that Anxa2 regulates HSC homing and binding to the bone marrow microenvironment and suggest that Anxa2 is crucial for determining the bone marrow niche of HSCs.

Leptin functions through a well-documented central neuroendocrine pathway to regulate bone mass. However, the ability of leptin to modulate bone mass through a peripheral mechanism has been debated due to conflicting in vitro results and lack of sufficient in vivo models. We utilized mice with LoxP sites introduced into the long-form leptin receptor (ObRb) gene to determine how leptin regulates mesenchymal progenitor cell (MPC) differentiation and osteoblast function in vitro and in vivo.