We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Paracrine Activation of STAT3 Drives GM-CSF Expression in Breast Carcinoma Cells, Generating a Symbiotic Signaling Network with Breast Carcinoma-Associated Fibroblasts.
- Authors
Osuala, Kingsley O.; Chalasani, Anita; Aggarwal, Neha; Ji, Kyungmin; Moin, Kamiar
- Abstract
Simple Summary: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a monomeric glycoprotein most commonly associated with myeloid cell differentiation and the stimulation of inflammatory processes. Several studies have shown that cancer cells express GM-CSF; however, the mechanism and effect of this expression has not been fully resolved. Some studies suggest the levels of GM-CSF expression and secretion determine its role in tumor suppression or growth. We believe and begin to outline in the current study, that breast cancer cell expression and secretion of GM-CSF is an operative pro-survival tool utilized to induce fibroblasts, macrophages, and other myeloid-derived cells to produce pro-inflammatory cytokines and growth factors such as interleukins 6 and 8. These pro-survival factors drive tumor progression. Understanding these paracrine signaling networks in the tumor microenvironment will facilitate the development of targeted and efficient therapies to halt tumor progression. This study evaluated the paracrine signaling between breast carcinoma-associated fibroblasts (CAFs) and breast cancer (BCa) cells. Resolving cell–cell communication in the BCa tumor microenvironment (TME) will aid the development of new therapeutics. Here, we utilized our patented TAME (tissue architecture and microenvironment engineering) 3D culture microphysiological system, which is a suitable pathomimetic avatar for the study of the BCa TME. We cultured in 3D BCa cells and CAFs either alone or together in cocultures and found that when cocultured, CAFs enhanced the invasive characteristics of tumor cells, as shown by increased proliferation and spread of tumor cells into the surrounding matrix. Secretome analysis from 3D cultures revealed a relatively high secretion of IL-6 by CAFs. A marked increase in the secretion of granulocyte macrophage-colony stimulating factor (GM-CSF) when carcinoma cells and CAFs were in coculture was also observed. We theorized that the CAF-secreted IL-6 functions in a paracrine manner to induce GM-CSF expression and secretion from carcinoma cells. This was confirmed by evaluating the activation of STAT3 and gene expression of GM-CSF in carcinoma cells exposed to CAF-conditioned media (CAF-CM). In addition, the treatment of CAFs with BCa cell-CM yielded a brief upregulation of GM-CSF followed by a marked decrease, indicating a tightly regulated control of GM-CSF in CAFs. Secretion of IL-6 from CAFs drives the activation of STAT3 in BCa cells, which in turn drives the expression and secretion of GM-CSF. As a result, CAFs exposed to BCa cell-secreted GM-CSF upregulate inflammation-associated genes such as IL-6, IL-6R and IL-8, thereby forming a positive feedback loop. We propose that the tight regulation of GM-CSF in CAFs may be a novel regulatory pathway to target for disrupting the CAF:BCa cell symbiotic relationship. These data provide yet another piece of the cell–cell communication network governing the BCa TME.
- Subjects
CANCER; CELL communication; CANCER invasiveness; MACROPHAGES; RESEARCH funding; BREAST tumors; CELL physiology; CELL proliferation; TISSUE engineering; CELLULAR signal transduction; CELL lines; GENE expression; FIBROBLASTS; CELL culture; GRANULOCYTE-macrophage colony-stimulating factor; GROWTH factors; STAT proteins; CYTOKINES; EXTRACELLULAR matrix; INFLAMMATION; INTERLEUKINS; DISEASE progression
- Publication
Cancers, 2024, Vol 16, Issue 16, p2910
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers16162910