Cancer-associated fibroblast-derived Gremlin 1 promotes breast cancer progression

Abstract

Background Bone morphogenetic proteins (BMPs) have been reported to maintain epithelial integrity and to antagonize the transforming growth factor β (TGFβ)-induced epithelial to mesenchymal transition. The expression of soluble BMP antagonists is dysregulated in cancers and interrupts proper BMP signaling in breast cancer. Methods In this study, we mined the prognostic role of BMP antagonists GREMLIN 1 (GREM1) in primary breast cancer tissues using in-house and publicly available datasets. We determined which cells express GREM1 RNA using in situ hybridization (ISH) on a breast cancer tissue microarray. The effects of Grem1 on the properties of breast cancer cells were assessed by measuring the mesenchymal/stem cell marker expression and functional cell-based assays for stemness and invasion. The role of Grem1 in breast cancer-associated fibroblast (CAF) activation was measured by analyzing the expression of fibroblast markers, phalloidin staining, and collagen contraction assays. The role of Grem1 in CAF-induced breast cancer cell intravasation and extravasation was studied by utilizing xenograft zebrafish breast cancer (co-) injection models. Results Expression analysis of clinical breast cancer datasets revealed that high expression of GREM1 in breast cancer stroma is correlated with a poor prognosis regardless of the molecular subtype. The large majority of human breast cancer cell lines did not express GREM1 in vitro, but breast CAFs did express GREM1 both in vitro and in vivo. Transforming growth factor β (TGFβ) secreted by breast cancer cells, and also inflammatory cytokines, stimulated GREM1 expression in CAFs. Grem1 abrogated bone morphogenetic protein (BMP)/SMAD signaling in breast cancer cells and promoted their mesenchymal phenotype, stemness, and invasion. Moreover, Grem1 production by CAFs strongly promoted the fibrogenic activation of CAFs and promoted breast cancer cell intravasation and extravasation in co-injection xenograft zebrafish models. Conclusions Our results demonstrated that Grem1 is a pivotal factor in the reciprocal interplay between breast cancer cells and CAFs, which promotes cancer cell invasion. Targeting Grem1 could be beneficial in the treatment of breast cancer patients with high Grem1 expression.

Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo

“…Grem1 is expressed by cells of the periepithelial intestinal mesenchymal sheath [ 17 ] and is functionally implicated in driving gastrointestinal carcinogenesis [ 21 ]. Stromal-derived Grem1 has also been implicated within the unique tumor microenvironment of other cancers including mesothelioma [ 22 ], pancreatic neuroendocrine tumors [ 23 ], mammary [ 24 ], uterine [ 25 ], cervical [ 26 ], and kidney [ 27 ] tumors. Furthermore, Grem1 has been found to be one of the most upregulated genes in the tumor microenvironment [ 28 ].…”

On-Target Anti-TGF-β Therapies Are Not Succeeding in Clinical Cancer Treatments: What Are Remaining Challenges?

“…Gremlin 1 (GREM1) is a BMP antagonist that binds to the ligand, preventing its interaction with membrane receptors and activation of downstream signaling pathway. As recently demonstrated by Ren et al (2019) elevated levels of GREM1 correlate with a poor prognostic for breast cancer patients. Also, the same study showed that GREM1 promotes EMT and invasion of breast cancer cells in vitro and it is correlated with higher levels of intravasation and extravasation in a zebrafish model.…”

“…Interestingly, the ability of breast cancer cells to overcome this anti metastatic mechanism was related to secretion of COCO (DAND5) and consequent inhibition of BMP signaling. Ren et al (2019), in the same study mentioned before, described that TGF-β-induced CAFs activation results in GREM1 (BMP inhibitor) secretion in vitro. This suggestive feed forward loop between CAFs and malignant cells was further reinforced by results showing that GREM1 expression is restricted to tumor stroma in breast cancer patients.…”

“…Tumor metastasis is a multistep process through which cancer cells leave their primary site to colonize distant organs (Zhou et al, 2014;Ren et al, 2019; Figure 1). In order to migrate and invade, epithelial cancer cells undergo phenotypic alterations to detach from surrounding cells, degrade the basement membrane and remodel the extracellular matrix (ECM) in a process known as epithelial-mesenchymal transition (EMT) (Nieto et al, 2016).…”

TrkB Inhibits the BMP Signaling-Mediated Growth Inhibition of Cancer Cells

“…For example, in an analysis of large patient cohorts, Gremlin 1, a BMP-antagonist, was found to be significantly increased in the tumor tissues of breast cancer patients [ 8 ]. In another study, Gremlin 1 was found to be responsible for the tumorigenic potential of cancer cells by inhibiting BMP/SMAD signaling, and its expression was associated with poor prognosis in breast cancer patients [ 9 ]. Moreover, estrogen treatment in these cells further reduced BMPRI expression [ 10 ], which, along with BMPRII, was also found to be significantly reduced in patients with poorly differentiated prostate, renal, and bladder cancers [ 5 , 11 , 12 ].…”