MINDIN secretion by prostate tumors induces premetastatic changes in bone via β-catenin

in Endocrine-Related Cancer

Correspondence should be addressed to V Alonso: veronica.alonsorodriguez@ceu.es

*(J A Ardura and L Álvarez-Carrión contributed equally to this work)

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Bone metastases are common in advanced prostate cancer patients, but mechanisms by which specific pro-metastatic skeletal niches are formed before tumor cell homing are unclear. We aimed to analyze the effects of proteins secreted by primary prostate tumors on the bone microenvironment before the settlement and propagation of metastases. Here, using an in vivo pre-metastatic prostate cancer model based on the implantation of prostate adenocarcinoma TRAMP-C1 cells in immunocompetent C57BL/6 mice, we identify MINDIN as a prostate tumor secreted protein that induces bone microstructural and bone remodeling gene expression changes before tumor cell homing. Associated with these changes, increased tumor cell adhesion to the endosteum ex vivo and to osteoblasts in vitro was observed. Furthermore, MINDIN promoted osteoblast proliferation and mineralization and monocyte expression of osteoclast markers. β-catenin signaling pathway revealed to mediate MINDIN actions on osteoblast gene expression but failed to affect MINDIN-induced adhesion to prostate tumor cells or monocyte differentiation to osteoclasts. Our study evidences that MINDIN secretion by primary prostate tumors creates a favorable bone environment for tumor cell homing before metastatic spread.

Supplementary Materials

    • Supplementary Figure 1. Expression of PSCA and mindin by TRAMP-C1 adenocarcinoma cells, MC3T3 osteoblastic cells and MLO-Y4 osteocytic cells (A and B). Mindin induces changes in bone remodeling markers in osteoblastic MC3T3-E1 and osteocytic MLO-Y4 cells prolonged (C-K) mindin stimulation (A) Prostate Stem Cell Antigen (PSCA) and (B) mindin mRNA expression were assessed by real time PCR. MC3T3-E1 cells (C-G) and MLO-Y4 (H-K) were stimulated with mindin (5ng/mL) for 15 days every 2 days. Total cell RNA was isolated to assess mRNA levels of OPG (C and H), RANK-L (D and I), Runx-2 (E and J), osteocalcin (F and K) and osterix (G) by real-time PCR. Experimental values are mean ± SEM from 3 independent experiments. *p< 0.05; **p< 0.01 vs MC3T3 and MLO-Y4 samples.
    • Suplementary Table 1. Protein profile of the secretome of MC3T3-E1 osteoblastic cells and MLO-Y4 osteocytic cells. Analysis of the protein secretome by RP-LC-MS/MS reveals absence of mindin (spondin-2) MC3T3-E1 (A) cells or MLO-Y4 (B) cells.

 

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