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

Abstract

Summary Stromal restraint of cancer growth and progression—emerging as a widespread phenomenon in epithelial cancers such as bladder, pancreas, colon, and prostate—appears rooted in stromal cell niche activity. During normal tissue repair, stromal niche signals, often Hedgehog-induced, promote epithelial stem cell differentiation as well as self-renewal, thus specifying regenerating epithelial pattern. In the case of cancerous tissue, stromal cell-derived differentiation signals in particular may provide a brake on malignant growth. Understanding and therapeutic harnessing of the role of stroma in cancer restraint may hinge on our knowledge of the signaling programs elaborated by the stromal niche.

Signaling in the stem cell niche: regulating cell fate, function and plasticity

“…Other cell types that signal in the niche Stromal cells within the niche are also active players in maintaining adult stem cells, acting via the secretion of key signaling factors such as WNT, Notch and BMP (Roberts et al, 2017). In the hair follicle, both the mesenchymal cells of the dermal papilla and dermal adipocyte precursor cells secrete factors that activate stem cells (Sennett and Rendl, 2012).…”

Pancreas organogenesis: The interplay between surrounding microenvironment(s) and epithelium-intrinsic factors

“…The mechanisms by which these mesenchymal signals are coordinated and integrated to stimulate epithelial progenitor proliferation and differentiation to produce functional pancreatic cells remain elusive. Also, whether is the developing pancreatic mesenchyme a homogenous tissue or composed of different mesenchymal cell populations, resembling distinct "cellular niches", like in the haematopoietic and nervous system, lungs and skin, is unclear (Crane et al, 2017;Kfoury and Scadden, 2015;Lattanzi et al, 2015;Roberts et al, 2017;Zepp et al, 2017 , Nkx3.2 and Hoxa6, Hoxb6 and Hoxc6 (Ahlgren et al, 1997;Asayesh et al, 2006;Hecksher-Sørensen et al, 2004;Landsman et al, 2011;Larsen et al, 2015). Isl1 is expressed in both pancreatic epithelium and mesenchyme and is required for dorsal mesenchyme formation (Ahlgren et al, 1997).…”

Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration

“…A critical role of SHH signaling in regulating adult stem cells has been explored in many self-renewing organs, including the prostate [13][14][15]. The regulation through paracrine interactions between stem cells and their surrounding niche has also been observed in prostate development, growth, and regeneration [16,17]. However, the precise mechanisms for SHH signaling in regulating prostatic stem/progenitor cells through a paracrine mechanism still remain unclear.…”