Abstract
The reciprocal interaction between cancer cells and the tissue-specific stroma is critical for primary and metastatic tumor growth progression. Prostate cancer cells colonize preferentially bone (osteotropism), where they alter the physiological balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, and elicit prevalently an osteoblastic response (osteoinduction). The molecular cues provided by osteoblasts for the survival and growth of bone metastatic prostate cancer cells are largely unknown. We exploited the sufficient divergence between human and mouse RNA sequences together with redefinition of highly species-specific gene arrays by computer-aided and experimental exclusion of cross-hybridizing oligonucleotide probes. This strategy allowed the dissection of the stroma (mouse) from the cancer cell (human) transcriptome in bone metastasis xenograft models of human osteoinductive prostate cancer cells (VCaP and C4-2B). As a result, we generated the osteoblastic bone metastasis-associated stroma transcriptome (OB-BMST). Subtraction of genes shared by inflammation, wound healing and desmoplastic responses, and by the tissue type-independent stroma responses to a variety of non-osteotropic and osteotropic primary cancers generated a curated gene signature (“Core” OB-BMST) putatively representing the bone marrow/bone-specific stroma response to prostate cancer-induced, osteoblastic bone metastasis. The expression pattern of three representative Core OB-BMST genes (PTN, EPHA3 and FSCN1) seems to confirm the bone specificity of this response. A robust induction of genes involved in osteogenesis and angiogenesis dominates both the OB-BMST and Core OB-BMST. This translates in an amplification of hematopoietic and, remarkably, prostate epithelial stem cell niche components that may function as a self-reinforcing bone metastatic niche providing a growth support specific for osteoinductive prostate cancer cells. The induction of this combinatorial stem cell niche is a novel mechanism that may also explain cancer cell osteotropism and local interference with hematopoiesis (myelophthisis). Accordingly, these stem cell niche components may represent innovative therapeutic targets and/or serum biomarkers in osteoblastic bone metastasis.
Highlights
Prostate cancer (PCa) is the most common solid cancer in men in the western world
Osteogenesis and angiogenesis are the key processes in the OBBMST and Core osteoblastic bone metastasisassociated stroma transcriptome (OB-BMST)
The gene ontology (GO) terms, the principal upstream regulators and the major effector cells of the OB-BMST and Core OB-BMST strongly indicate that osteogenesis and angiogenesis are the predominant processes in the bone marrow/bone (BM/B) stroma reaction of PCainduced, osteoblastic bone metastasis
Summary
Prostate cancer (PCa) is the most common solid cancer in men in the western world. Despite early detection and surgical treatment of the tumor, 10–20% of PCa patients show bone metastases at diagnosis [1] and .80% of advanced PCa patients have bone metastases at autopsy [2]. In primary and metastatic cancers neoplastic cells closely interact with different cell types and the extracellular matrix (ECM) constituting the stroma compartment. This leads to activation of the stroma and, in turn, to the secretion of additional growth factors, matrix proteins and proteases, which further favor cancer cell proliferation and invasion. These heterogeneous and bi-directional interactions within the tumor tissue are fundamental for tumor growth progression [3]. Elucidation of the mechanism(s) determining the initiation and progression of metastatic growth is essential for the identification of novel therapeutic targets for prevention and/or treatment of cancer metastases
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