ABSTRACT
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.
Subject(s)
Bone Marrow Neoplasms/secondary , Hematopoietic Stem Cells/pathology , Prostatic Neoplasms , Animals , Bone Marrow Neoplasms/pathology , Bone Marrow Transplantation , Cell Line, Tumor , Humans , Male , Mice , Mice, Inbred NOD , Mice, SCID , Models, Biological , Neoplasm Transplantation , Osteoblasts/pathology , Prostatic Neoplasms/pathology , Tissue Donors , Transplantation, HeterologousABSTRACT
BACKGROUND: It 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 FINDINGS: In 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/SIGNIFICANCE: These 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 hematopoiesis and osteopoiesis in the marrow.
Subject(s)
Erythropoietin/metabolism , Hematopoiesis , Osteogenesis , Animals , Animals, Newborn , Bone Marrow Cells/cytology , Bone Marrow Cells/drug effects , Bone Marrow Cells/metabolism , Bone Morphogenetic Proteins/metabolism , Erythropoietin/pharmacology , Hematopoiesis/drug effects , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Humans , Mice , Mice, Inbred C57BL , Models, Biological , Osteoblasts/cytology , Osteoblasts/drug effects , Osteoblasts/metabolism , Osteoclasts/cytology , Osteoclasts/drug effects , Osteoclasts/metabolism , Osteogenesis/drug effects , Phenotype , Receptors, Erythropoietin/metabolism , Stromal Cells/drug effects , Stromal Cells/metabolismABSTRACT
Our recent studies have shown that annexin II, expressed on the cell surface of osteoblasts, plays an important role in the adhesion of hematopoietic stem cells (HSCs) to the endosteal niche. Similarly, prostate cancer (PCa) cells express the annexin II receptor and seem to use the stem cell niche for homing to the bone marrow. The role of the niche is thought to be the induction and sustenance of HSC dormancy. If metastatic PCa cells occupy a similar or the same ecological niche as HSCs, then it is likely that the initial role of the HSC niche will be to induce dormancy in metastatic cells. In this study, we demonstrate that the binding of PCa to annexin II induces the expression of the growth arrest-specific 6 (GAS6) receptors AXL, Sky, and Mer, which, in the hematopoietic system, induce dormancy. In addition, GAS6 produced by osteoblasts prevents PCa proliferation and protects PCa from chemotherapy-induced apoptosis. Our results suggest that the activation of GAS6 receptors on PCa in the bone marrow environment may play a critical role as a molecular switch, establishing metastatic tumor cell dormancy.
Subject(s)
Intercellular Signaling Peptides and Proteins/metabolism , Neoplasm Invasiveness , Prostatic Neoplasms/metabolism , Stem Cell Niche/metabolism , Animals , Annexin A2/metabolism , Apoptosis/physiology , Blotting, Western , Cell Line, Tumor , Cell Proliferation , Cell Separation , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Immunohistochemistry , Male , Mice , Osteoblasts/metabolism , Prostatic Neoplasms/pathology , Receptor Protein-Tyrosine Kinases , Reverse Transcriptase Polymerase Chain Reaction , Stem Cell Niche/cytology , Tissue Array AnalysisABSTRACT
One of the most life-threatening complications of prostate cancer is skeletal metastasis. In order to develop treatment for metastasis, it is important to understand its molecular mechanisms. Our work in this field has drawn parallels between hematopoietic stem cell and prostate cancer homing to the marrow. Our recent work demonstrated that annexin II expressed by osteoblasts and endothelial cells plays a critical role in niche selection. In this study, we demonstrate that annexin II and its receptor play a crucial role in establishing metastasis of prostate cancer. Prostate cancer cell lines migrate toward annexin II and the adhesion of prostate cancer to osteoblasts and endothelial cells was inhibited by annexin II. By blocking annexin II or its receptor in animal models, short-term and long-term localization of prostate cancers are limited. Annexin II may also facilitate the growth of prostate cancer in vitro and in vivo by the MAPK pathway. These data strongly suggest that annexin II and its receptor axis plays a central role in prostate cancer metastasis, and that prostate cancer utilize the hematopoietic stem cell homing mechanisms to gain access to the niche.
