VEGF-A and Tenascin-C produced by S100A4 ⁺ stromal cells are important for metastatic colonization

Abstract

Increased numbers of S100A4 + cells are associated with poor prognosis in patients who have cancer. Although the metastatic capabilities of S100A4 + cancer cells have been examined, the functional role of S100A4 + stromal cells in metastasis is largely unknown. To study the contribution of S100A4 + stromal cells in metastasis, we used transgenic mice that express viral thymidine kinase under control of the S100A4 promoter to specifically ablate S100A4 + stromal cells. Depletion of S100A4 + stromal cells significantly reduced metastatic colonization without affecting primary tumor growth. Multiple bone marrow transplantation studies demonstrated that these effects of S100A4 + stromal cells are attributable to local non-bone marrow-derived S100A4 + cells, which are likely fibroblasts in this setting. Reduction in metastasis due to the loss of S100A4 + fibroblasts correlated with a concomitant decrease in the expression of several ECM molecules and growth factors, particularly Tenascin-C and VEGF-A. The functional importance of stromal Tenascin-C and S100A4+ fibroblast-derived VEGF-A in metastasis was established by examining Tenascin-C null mice and transgenic mice expressing Cre recombinase under control of the S100A4 promoter crossed with mice carrying VEGF-A alleles flanked by loxP sites, which exhibited a significant decrease in metastatic colonization without effects on primary tumor growth. In particular, S100A4+ fibroblast-derived VEGF-A plays an important role in the establishment of an angiogenic microenvironment at the metastatic site to facilitate colonization, whereas stromal Tenascin-C may provide protection from apoptosis. Our study demonstrates a crucial role for local S100A4 + fibroblasts in providing the permissive "soil" for metastatic colonization, a challenging step in the metastatic cascade.stromal fibroblasts | metastasis-associated fibroblasts | tumor microenvironment | metastatic microenvironment A bout 90% of cancer deaths are attributable to systemic disease associated with metastasis (1). Among the steps involved in metastasis, the colonization step is considered the most challenging for an invading cancer cell (2). With metastatic disease as the leading cause of death among patients who have cancer (3), a greater need is emphasized for a better understanding of the metastatic process so as to identify efficacious cancer therapies. S100A4 (also known as CAPL, p9Ka, 42A, pEL98, mts1, metastasin, calvasculin, 18A2, or FSP1) is a member of the S100 calcium-binding family, which has a high prognostic significance for metastasis in patients with cancer (4). Several studies have demonstrated a correlation between increased numbers of S100A4 + cells and poor prognosis of patients for a variety of cancer types, including colorectal adenocarcinoma, non-small cell lung cancer, breast adenocarcinoma, gastric cancer, esophageal squamous carcinoma, bladder cancer, prostate adenocarcinoma, melanoma, and ovarian carcinoma. Although S100A4 + cells encompass a variety of cell types, including malignant c...

Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival

“…Previous studies have identified cancer-associated fibroblasts as a major source of Tnc in tumors (39), but whether stroma-derived Tnc has a role in tumor progression in this model is unclear. Although the precise mechanism of action remains to be elucidated, we have shown that Tnc is a target of the transcription factor Nkx2-1, which has been shown to suppress lung cancer progression and metastasis through the suppression of embryonic genes (19).…”

S100A4 promotes colon inflammation and colitis-associated colon tumorigenesis

“…31 Furthermore, it has been demonstrated that the ablation of S100A4 in stromal cells significantly reduced metastatic colonization by regulating matrix protein tenascin-C and growth factor vascular endothelial growth factor (VEGF)-A. 32 In previous studies, we found an additional mechanism of action that S100A4 + fibroblasts promote skin carcinogenesis by maintaining MCP-1-mediated macrophage infiltration and chronic inflammation. 20 In addition, we identified a critical role of S100A4 in promoting liver fibrosis through hepatic stellate cell activation, 21 and macrophage-derived S100A4 promotes liver carcinogenesis by promoting CD8 + T-cell survival (unpublished).…”

Tenascin-C: Exploitation and collateral damage in cancer management

“…This hypothesis is supported by data showing that VEGFA is instrumental in tenascin-C enhanced lung metastasis of 4T1 cells. 105 Yet a potential link to radiotherapy still has to be investigated.…”