The secreted matrix protein mindin increases prostate tumor progression and tumor-bone crosstalk via ERK 1/2 regulation

Carcinogenesis. 2019 Jul 20;40(7):828-839. doi: 10.1093/carcin/bgz105.

Abstract

Advanced prostate cancer cells preferentially metastasize to bone by acquiring a bone phenotype that allows metastatic cells to thrive in the skeletal environment. Identification of factors that promote the expression of ectopic bone genes-process known as osteomimicry-leading to tumor progression is crucial to prevent and treat metastatic prostate cancer and prolong life expectancy for patients. Here, we identify the extracelular matrix protein mindin in the secretome of prostate adenocarcinoma cells and show that mindin overexpression in human and mouse TRAMP-C1-induced prostate tumors correlates with upregulated levels of bone-related genes in the tumorigenic prostate tissues. Moreover, mindin silencing decreased osteomimicry in adenocarcinoma cells and in the prostate tumor mice model, as well as reduced tumor cell proliferation, migration and adhesion to bone cells. Inhibition of the extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation decreased the proliferative, migratory and pro-adhesion actions of mindin on prostate tumor cells. In addition, conditioned media obtained by crosstalk stimulation of either osteocytes or osteoblasts with the secretome of TRAMP-C1 cells promoted osteomimicry in prostate tumor cells; an effect inhibited by mindin silencing of TRAMP-C1 cells. In vivo, tibiae of primary tumor-bearing mice overexpressed the pro-angiogenic and pro-metastattic factor vascular endothelial growth factor receptor 2 (VEGFR2) in a mindin-dependent manner. Our findings indicate that mindin is a novel regulator of osteomimicry in prostate tumors and potentially mediates tumor-bone cell crosstalk, suggesting its promising role as a target to inhibit bone metastases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology*
  • Animals
  • Bone Neoplasms / pathology
  • Bone Neoplasms / secondary*
  • Bone and Bones / cytology
  • Bone and Bones / pathology*
  • Carcinogenesis / pathology
  • Cell Adhesion
  • Cell Communication
  • Cell Line, Tumor / transplantation
  • Cell Proliferation
  • Disease Models, Animal
  • Disease Progression
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Osteoblasts / pathology
  • Osteocytes / pathology
  • Phosphorylation
  • Prostate / cytology
  • Prostate / pathology
  • Prostatic Neoplasms / pathology*
  • Up-Regulation
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Extracellular Matrix Proteins
  • Neoplasm Proteins
  • SPON2 protein, human
  • Spon2 protein, mouse
  • mindin
  • Kdr protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2