Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy

Abstract

Glioblastomas are the most prevalent and lethal primary brain tumor and are comprised of hierarchies with selfrenewing cancer stem cells (CSCs) at the apex. Like neural stem cells (NSCs), CSCs reside in functional niches that provide essential cues to maintain the cellular hierarchy. Bone morphogenetic proteins (BMPs) instruct NSCs to adopt an astrocyte fate and are proposed as anti-CSC therapies to induce differentiation, but, paradoxically, tumors express high levels of BMPs. Here we demonstrate that the BMP antagonist Gremlin1 is specifically expressed by CSCs as protection from endogenous BMPs. Gremlin1 colocalizes with CSCs in vitro and in vivo. Furthermore, Gremlin1 blocks prodifferentiation effects of BMPs, and overexpression of Gremlin1 in non-CSCs decreases their endogenous BMP signaling to promote stem-like features. Consequently, Gremlin1-overexpressing cells display increased growth and tumor formation abilities. Targeting Gremlin1 in CSCs results in impaired growth and self-renewal. Transcriptional profiling demonstrated that Gremlin1 effects were associated with inhibition of p21, a key CSC signaling node. This study establishes CSC-derived Gremlin1 as a driving force in maintaining glioblastoma tumor proliferation and glioblastoma hierarchies through the modulation of endogenous prodifferentiation signals.

Cancer stem cells in glioblastoma

“…Despite the presence of BMP expression in primary GBM tissue, glioma CSCs are highly resistant to the differentiation effects of BMPs in a process that occurs through at least two distinct cell-autonomous mechanisms: the shift to a fetal BMP receptor expression in glioma CSCs through recruitment of the transcriptional repressor EZH2 ) and the secretion of BMP antagonists, specifically Gremlin1, by CSCs to protect against endogenous BMPmediated differentiation (Yan et al 2014). In this manner, CSCs generate differentiated progeny that provide supportive cues to the parental cells (e.g., Notch ligands, interleukin-6 [IL-6], and extracellular matrix) while resisting differentiation signals.…”

“…In a manner that mimics aberrant differentiation, CSCs co-opt developmental programs to maintain an undifferentiated state, increasing their survival and maintenance. Common pathways activated in CSCs include Notch, BMP, NF-κB, and Wnt signaling (Li et al 2009a;Day et al 2013;Rheinbay et al 2013;Lubanska et al 2014;Yan et al 2014). Collectively, niche factors represent an overriding theme in CSC biology, where stem and progenitor cell features provide selective advantages to maintain tumor growth (Fig.…”

Investigation of GREMLIN 1, COL15A1 immunoreactivity and the relationship between microvessel density and GREMLIN 1 in papillary renal cell carcinoma and chromophobe renal cell carcinoma

“…Karagiannis et al (16) showed that GREM1 promotes the loss of cancer cell differentiation at the cancer invasion front, a mechanism that may facilitate tumor progression. Yan et al (17) reported that Gremlin1-overexpressing cells display increased growth and tumor formation abilities. In our study, the association between GREM1 expression and angiogenesis was examined in tumor tissues using numerical values of microvascular structures (MVD) stained with COL15A1 taking into account the fact that COL15A1 serves as an endothelial marker.…”

Gremlin1 and chronic pancreatitis: a new clinical target and biomarker?

“…This pro-fibrotic signalling is counteracted by BMP-2 signalling, which in turn is inhibited by increased Gremlin1 expression from PSCs triggered by TGF-β1 and other factors. Thus, increased Gremlin1 is both a driver and marker of fibrosis during chronic pancreatitis cancer stem cell (CSC) pluripotency, which has been implicated in colon cancer and glioma initiation and development [26,27]. Thus, pharmacological targeting of Gremlin1 in this scenario would drive CSCs towards a more differentiated tumour cell type that would be more susceptible to chemotherapy and radiotherapy agents [27].…”

“…Thus, increased Gremlin1 is both a driver and marker of fibrosis during chronic pancreatitis cancer stem cell (CSC) pluripotency, which has been implicated in colon cancer and glioma initiation and development [26,27]. Thus, pharmacological targeting of Gremlin1 in this scenario would drive CSCs towards a more differentiated tumour cell type that would be more susceptible to chemotherapy and radiotherapy agents [27]. Given that CP progresses to pancreas cancer in approximately 7 % of patients, this suggests that Gremlin1 may have overlapping roles in both fibrosis and cancer.…”