Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth

Abstract

A role for Hedgehog (Hh) signalling in the development of colorectal cancer (CRC) has been proposed. In CRC and other solid tumours, Hh ligands are upregulated; however, a specific Hh antagonist provided no benefit in a clinical trial. Here we use Hh reporter mice to show that downstream Hh activity is unexpectedly diminished in a mouse model of colitis-associated colon cancer, and that downstream Hh signalling is restricted to the stroma. Functionally, stroma-specific Hh activation in mice markedly reduces the tumour load and blocks progression of advanced neoplasms, partly via the modulation of BMP signalling and restriction of the colonic stem cell signature. By contrast, attenuated Hh signalling accelerates colonic tumourigenesis. In human CRC, downstream Hh activity is similarly reduced and canonical Hh signalling remains predominantly paracrine. Our results suggest that diminished downstream Hh signalling enhances CRC development, and that stromal Hh activation can act as a colonic tumour suppressor.

Control of inflammation by stromal Hedgehog pathway activation restrains colitis

“…Additionally, we have demonstrated that stromal genetic or pharmacologic Hh pathway activation can reduce tumor burden in the AOM-DSS colon cancer model, as also recently reported elsewhere (30). Hence, the beneficial effects of Hh-mediated suppression of inflammation also extend to its downstream sequelae, namely progression to adenocarcinoma.…”

The Stromal Niche for Epithelial Stem Cells: A Template for Regeneration and a Brake on Malignancy

“…For bladder, we review evidence that niche-derived differentiation factors play an important role in restraining bladder cancer progression (Shin et al, 2014). Finally, we connect these studies to recent work demonstrating a surprisingly general cancer-restraining effect of stromal Hedgehog response in organs where the stem cells or their stromal niches are less well defined (Gerling et al, 2016; Lee et al, 2014; Rhim et al, 2014; Shin et al, 2014; Yang et al, 2016). …”

“…Potentially explaining the disappointing results of these clinical trials, recent work has shown a surprisingly general effect of stromal Hedgehog response in restraining cancer growth and progression, most notably in bladder (Shin et al, 2014), pancreatic (Lee et al, 2014; Rhim et al, 2014), colon (Gerling et al, 2016; Lee et al, 2016), and prostate (Yang et al, 2016) cancers. From these studies, several common themes emerge: (1) Hh signaling occurs in a paracrine fashion, with epithelial cells producing Hedgehog ligand and pathway activity exclusively restricted to stromal cells; and (2) Hedgehog pathway activation in stromal cells restrains growth and progression of primary epithelial tumors.…”

“…At the same time, recent studies have identified a surprising role for stroma, which includes the niche cells for several populations of epithelial stem cells, in restraint of epithelial cancer growth and progression in multiple organs including bladder (Shin et al, 2014), pancreas (Lee et al, 2014; Özdemir et al, 2014; Rhim et al, 2014), colon (Gerling et al, 2016; Lee et al, 2016), and prostate (Yang et al, 2016). Taken together with our expanded understanding of the stromal niche as an active player in promoting differentiation of adult stem cells, these findings implicate niche-derived differentiative cues as potential barriers to malignant growth.…”

Transcriptional Regulation of the Intestinal Cancer Stem Cell Phenotype

“…Moreover, IHH gene knock-out leads to intestinal SC accumulation [57]. In addition, specific Hh activation in murine stromal cells induces complex transcriptional changes, leading to loss of colon SC-specific gene expression and upregulation of epithelial differentiation markers [58]. Most of the components of the Hh signaling pathway are upregulated (mRNA and protein) in CRC, with the exception of IHH that appears to be downregulated.…”