Breast Carcinoma–associated Fibroblasts Share Similar Biomarker Profiles in Matched Lymph Node Metastasis

Abstract

This study sought to understand the role of breast carcinoma-associated fibroblasts in the progression of cancer cells into lymph nodes. We compared fibroblasts of primary tumors and matched the involved lymph nodes to select fibroblast activation markers, namely α-smooth muscle actin (α-SMA), S100A4, and vimentin, as well as to determine the frequency of transforming growth factor β1, a pleiotropic cytokine that induces the differentiation of fibroblasts to myofibroblasts, and its downstream effectors: CXCR4 and p-AKT. We disposed samples of 80 primary invasive ductal carcinomas and matched the involved lymph nodes from 43 cases into 3 tissue microarrays, and analyzed stromal and tumor epithelial cells separately by immunohistochemistry. Control uninvolved lymph nodes were analyzed by whole-tissue sections. Cancer-associated fibroblast in lymph nodes with macrometastasis expressed similar profiles of vimentin, α-SMA, and S100A4 as those found in primary tumors. Cancer-associated fibroblast were uniformly estrogen receptor, progesterone receptor, HER-2, Ki-67, and p53 negative, but expressions of transforming growth factor β1 (TGFβ1), CXCR4, and p-AKT staining (62.3%, 52.4%, 65%, respectively) were equivalent between primary and lymph node metastasis (LNM) fibroblasts. A significant coexpression of TGFβ1 with p-AKT and CXCR4 in LNMs suggested the involvement of these proteins with TGFβ1 signaling. These biomarkers, including α-SMA and S100A4, were negative in fibroblasts of cancer-free lymph nodes, with the exception of vimentin. Our finding that expressions of biological markers were similar in fibroblasts of the primary tumors and in matched LNMs, but were absent in cancer-free lymph nodes, supports the assumption that the lymph node stroma mimics the microenvironment observed in primary tumors.

Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms

“…The four CAF subsets we identified in LN mirror CAF subpopulations in PTs 32,33 . This is consistent with studies showing that LN stroma mimics PT microenvironment 28,30 . But, our results provide new insights.…”

“…CAFs are poorly described in metastases, including axillary LN metastases, with only few studies assessing some markers, such as podoplanin (PDPN) or α-smooth muscle actin (αSMA) [27][28][29][30] . CAFs are known to be heterogeneous in PTs [31][32][33][34] , but characterization of this heterogeneity and its link with CAF functions is still far from being understood.…”

The Expression of Fibroblast Activation Protein in Clear Cell Renal Cell Carcinomas Is Associated with Synchronous Lymph Node Metastases

“…Within the lymph nodes, CAFs share similar biomarker profiles than in primary tumors [28]. In our study, FAP was also significantly expressed in nodal CAFs, suggesting that microenvironments in mCCRCC are similar in primary tumor and in lymph nodes [27,28]. …”

Stromal-epithelial lactate shuttle induced by tumor‑derived interleukin‑1β promotes cell proliferation in oral squamous cell carcinoma

“…CAFs, also known as activated fibroblasts, are the biggest population of cancer stromal cells and differ from NFs in many respects, particularly epigenetics ( 12 ). For example, CAFs usually present with a caveolin-1 (cav-1) loss ( 13 ) and express active markers such as α-SMA, stromal cell derived factor-1 ( 14 ) and fibroblast activation protein ( 15 ). Gene expression analysis demonstrated that the activated fibroblasts, CAFs, secrete a large amount of proteins and enzymes that disrupt the extracellular matrix, recruit immunocytes, and promote angiogenesis and metastasis ( 16 ).…”