Journal Article

The Molecular Signature of the Stroma Response in Prostate Cancer-Induced Osteoblastic Bone Metastasis Highlights Expansion of Hematopoietic and Prostate Epithelial Stem Cell Niches

Delorenzi, Mauro, Özdemir, Berna C., Temanni, Ramzi, Fleischmann, Achim, Poch, Olivier, Secondini, Chiara, Mills, Ian G., Cecchini, Marco G., Hensel, Janine, van der Pluijm, Gabri, Thalmann, George N., Wetterwald, Antoinette, Raffelsberger, Wolfgang, Schwaninger, Ruth

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Biochemistry, Molecular Biology / Bioinformatics / Biology and Life Sciences / Biomarkers / Biomarkers, Tumor - genetics / Biomarkers, Tumor - metabolism / Bone marrow / Bone Neoplasms - genetics / Bone Neoplasms - metabolism / Bone Neoplasms - secondary / Bone resorption / Bones / Breast cancer / Cancer metastasis / Cell Differentiation / Development and progression / DNA microarrays / Epithelial Cells - metabolism / Epithelial Cells - pathology / Gene expression / Gene Expression Profiling / Hematopoietic stem cells / Hematopoietic System - metabolism / Hematopoietic System - pathology / Humans / Hybridization / Hypotheses / Immunoenzyme Techniques / Laboratories / Life Sciences / Male / Medical innovations / Medical research / Medicine and Health Sciences / Metastasis / Mice / Neovascularization, Pathologic - genetics / Niches / Oligonucleotide Array Sequence Analysis / Oligonucleotides / Osteoblasts - metabolism / Osteoblasts - pathology / Osteogenesis - genetics / Physiological aspects / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - pathology / Real-Time Polymerase Chain Reaction / Research and Analysis Methods / Reverse Transcriptase Polymerase Chain Reaction / RNA, Messenger - genetics / Stem Cell Niche - genetics / Stem cells / Stromal Cells - metabolism / Stromal Cells - pathology / Therapeutic applications / Tumor Cells, Cultured / Tumors / Urology / Xenografts