Selection of Bone Metastasis Seeds by Mesenchymal Signals in the Primary Tumor Stroma

Abstract

Summary How organ-specific metastatic traits arise in primary tumors remains unknown. Here we show a role of the breast tumor stroma in selecting cancer cells that are primed for metastasis in bone. Cancer-associated fibroblasts (CAFs) in triple-negative (TN) breast tumors skew heterogeneous cancer cell populations towards a predominance of clones that thrive on the CAF-derived factors CXCL12 and IGF1. Limiting concentrations of these factors select for cancer cells with high Src activity, a known clinical predictor of bone relapse and an enhancer of PI3K-Akt pathway activation by CXCL12 and IGF1. Carcinoma clones selected in this manner are primed for metastasis in the CXCL12-rich microenvironment of the bone marrow. The evidence suggests that stromal signals resembling those of a distant organ select for cancer cells that are primed for metastasis in that organ, thus illuminating the evolution of metastatic traits in a primary tumor and its distant metastases.

Inflammation and skeletal metastasis

“…Although the bone is a frequent target site for several types of cancer such as prostate and breast cancers, 152 only recently are the signals that direct bone-specific metastasis beginning to be understood. 26,153,154 Importantly, in a dormancy model of bone-metastatic breast cancer, activation of the NF-kB pathway in tumor cells induced the expression of the vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 attracted the Tumor microenvironment and inflammation H Roca and LK McCauley a4 þ b1 þ -monocytic myeloid (CD11b þ ) cells containing osteoclast progenitors to enhance osteoclast differentiation and activity and to promote bone-metastatic colonization.…”

“…138 Other studies suggest that cancer cells preferentially metastasize at sites at which the expression of specific tumorpromoting factors mimics the primary tumor conditions. 26 Accordingly, myeloid cells may function as the initial 'task force' that selects and prepares the future metastatic site to resemble the primary site, a process that could be enhanced by tumor self-seeding. 58 Recent findings suggest another mechanism that leads to STAT3 activation in bone marrow-derived macrophages.…”

“…25 CAFs are also involved in the homing of metastatic cells to the bone marrow through the expression of CXCL12 and insulin-like growth factor 1 (IGF-1), which are responsible for the selection of the metastatic cells directed to high CXCL12-expressing microenvironment. 26 Fibroblasts isolated from mouse models of squamous-cell carcinoma, mammary and pancreatic cancers showed a proinflammatory gene signature including the tumor-promoting cytokines (such as IL-6, IL-1b), chemoattractants of macrophages and neutrophils (CXCL1, CXCL2 and CXCL5) and matrix-modifying proteases (such as matrix metalloproteinase 3 (MMP3) and MMP12). Inflammatory CAFs demonstrated the activation of nuclear factor-kB (NF-kB) signaling responsible for high macrophage infiltration, enhanced angiogenesis and tumor growth.…”

Contrôle de la croissance et de la dissémination tumorales par le microenvironnement

“…Le stroma des tumeurs primaires joue donc un rôle important de stimulant de la croissance et de la dissémination tumorales. De manière plus inattendue, les CAF seraient capables de sélectionner, dans les tumeurs mammaires primaires, un type de cellules tumorales capables de disséminer préférentiellement dans l'os [30]. De plus, les TAM peuvent fusionner avec les cellules néo-plasiques, créant ainsi des cellules hybrides ayant acquis un pouvoir migratoire accru, semblable à celui des macrophages [3].…”

Tumour-derived miRNAs and bone metastasis

“…A small subset of cancer cells in breast primary tumours express specific gene signatures that would be predictive of bone metastasis. 14,15 In this respect, the identification of miRNA and gene signatures expressed in primary carcinomas and their matching bone metastases would provide information on molecular mechanisms driving bone metastasis. It is very likely that before patients are diagnosed with cancer, dormant disseminated tumour cells (DTC) are already present in the bone marrow.…”