CD26 expression is attenuated by TGF‐β and SDF‐1 autocrine signaling on stromal myofibroblasts in human breast cancers

Abstract

Human breast carcinoma‐associated fibroblasts (CAFs) increasingly acquire both transforming growth factor‐β (TGF‐β) and stromal cell‐derived factor‐1 (SDF‐1) signaling in an autocrine fashion during tumor progression. Such signaling mediates activated myofibroblastic and tumor‐promoting properties in these fibroblasts. CD26/dipeptidyl peptidase‐4 is a serine protease that cleaves various chemokines including SDF‐1. Stromal CD26 expression is reportedly undetectable in human skin squamous cell carcinomas. However, whether stromal CD26 expression is also downregulated in human breast cancers and which stromal cells potentially lack CD26 expression remain elusive. To answer these questions, sections prepared from 239 human breast carcinomas were stained with antibodies against CD26 and α‐smooth muscle actin (α‐SMA), a marker for activated myofibroblasts. We found that tumor‐associated stroma involving α‐SMA‐positive myofibroblasts stained negative or negligible for CD26 in 118 out of 193 (61.1%) tumors, whereas noncancerous stromal regions of the breast showed considerable staining for CD26. This decreased stromal CD26 staining in tumors also tends to be associated with poor outcomes for breast cancer patients. Moreover, we demonstrated that CD26 staining is attenuated on stromal myofibroblasts in human breast cancers. Consistently, CD26 expression is significantly downregulated in cultured CAF myofibroblasts extracted from human breast carcinomas as compared to control human mammary fibroblasts. Inhibition of TGF‐β or SDF‐1 signaling in CAFs by shRNA clearly upregulated the CD26 expression. Taken together, these findings indicate that CD26 expression is attenuated by TGF‐β‐ and SDF‐1‐autocrine signaling on stromal myofibroblasts in human mammary carcinomas, and that decreased stromal CD26 expression has potential as a prognostic marker.

TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts

“…3c-e). Likewise, a similar phenomenon was recently described in fibroblasts from human pancreatic and breast carcinoma 37,51 , suggesting some resemblance across different murine and human tumor types.…”

Deciphering the temporal heterogeneity of cancer-associated fibroblast subpopulations in breast cancer

“…On the contrary, a recent study in human breast cancer demonstrated a considerable lower expression of CD26 in αSMA-rich tumour areas, as compared to the noncancerous stromal regions of the breast. Despite the reduced CD26 expression observed in this study, 75 out of 193 patients still expressed moderate/significant levels of CD26 in the breast tumours [51]. Interestingly, the study suggested that TGF-β and SDF-1 signalling suppresses CD26 expression in CAFs, and it will therefore be important to characterise the biological role of CD26+ CAF populations during immune suppression and contractile/ECM remodelling.…”

Fibroblasts direct differentiation of human breast epithelial progenitors

“…While this concurs with our early studies, which suggested diverse cellular origins of CAFs, including resident broblasts and perivascular cells [62,63], our present ndings suggest that lineage heterogeneity within the resident broblast compartment adds to the complexity. If indeed this is the case and myo broblast and in ammatory classi cation operate among both CAFs and normal resident broblasts, it is tempting to speculate on lineage interrelationships and how these may be taken advantage of in a clinical setting [64]. The cell lines established in the present study may prove valuable in determining such lineage relationships.…”