TGF-β Receptor II Loss Promotes Mammary Carcinoma Progression by Th17-Dependent Mechanisms

Abstract

We report that IL-17 significantly increases the secretion of CXCL1 and CXCL5 from mammary carcinoma cells, which is downregulated by TGF-β through the type II TGF-β receptor (TβRII). Carcinoma cells with conditional knockout of TβRII (Tgfbr2KO) have enhanced sensitivity to IL-17a in the stimulation of chemokine secretion. During polyoma middle T (PyMT) induced tumor progression, levels of Th17 inducing cytokines TGF-β, IL-6, IL-23 were increased in PyMT/Tgfbr2KO tumors, which was associated with an increased number of Th17 cells. IL-17 increased the suppressive function of MDSCs on T cells through the upregulation of Arg, IDO, and COX2. Treatment of PyMT/Tgfbr2KO mice with anti-IL-17 Ab decreased carcinoma growth and metastatic burden. Analysis of human breast cancer transcriptome databases showed a strong association between IL-17 gene expression and poor outcome in lymph node positive, estrogen receptor negative or luminal B subtypes suggesting potential therapeutic approaches.

Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis

“…In the bone metastasis microenvironment, breast tumor associated osteoblasts (TAOs) secrete CXCL5 to mediate cancer development via the ERK/MSK1/Elk-1/Snail signaling pathway [34]. As mentioned above, (IL)-17 significantly increases secretion of CXCL1 and CXCL5 from breast carcinoma cells, suppressing the function of MDSCs [35]. As its former name granulocyte protein 2 (GCP-2) indicates, CXCL6 is a chemoattractant for neutrophils.…”

Regulation of Tumor Metastasis by Myeloid-Derived Suppressor Cells

“…IL-17 increased the immune-suppressive function of MDSC through the up-regulation of arg-1, MMP-9, indoleamine 2,3-dioxygenase (IDO), and COX-2 (52). Transmembrane but not secreted TNF-α enhanced suppressive activity of MDSC by up-regulating arg-1 and inducible NO synthase (iNOS), promoting secretion of NO, ROS, IL-10, and TGF-β (53).…”

The wound healing, chronic fibrosis, and cancer progression triad

“…Although it acts through different cells and mechanisms and clearly participates as a tumor suppressor at early tumorigenic stages, it is nevertheless clear that TGF-␤ also promotes fibrosis (238) as well as tumor progression and metastasis (242). Certainly more information is needed in this regard as knockout of the TGF-␤ receptor II was shown to have tumorpromoting consequences (271), while collective cell migration was shown to improve under TGF-␤ signaling depletion (243). Nonetheless, TGF-␤ is evidently the most dominant profibrogenic factor known in all tissues, and anti-TGF-␤ agents (see Supplemental Table S2) are highly effective in a variety of fibrosis models.…”