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

Abstract

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 a 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.

Keywords: cancer progression; differentiation therapy; epithelial stem cell niche; epithelial stromal signaling; hedgehog signaling; regeneration.

Figure 1. Gli activity is a coordinator of the stromal niche in bladder and mammary gland

A. Bladder. Shh derived from bladder epithelium, upregulated in response to injury, activates Gli transcription factors in the bladder stroma, which induce transcription of secreted factors including proliferative factors (Wnt2/4) and differentiative factors (Bmp4/5) that regulate the activity of epithelial stem cells. B. Mammary gland. Tgfβ produced by mammary epithelial cells induces expression in adjacent stromal cells of the major Hedgehog pathway transcriptional effector, Gli2. Gli2 in turn activates transcription of receptors for the mammatrophic hormones estrogen and growth hormone (Esr1, Ghr), thereby entraining the niche to regulation by mammatrophic hormones that control pubertal growth. The targets that respond to Gli2 and/or mammatrophic hormones include a set of secreted paracrine signals (Wnt2, Igf1, Hgf, Fgf7, Bmp7), some of which are known to support mammary epithelial stem cell proliferation/renewal, and others likely to play roles in differentiation and ductal morphogenesis.

Figure 2. Model of niche dysfunction in cancer progression

A. During normal homeostasis or injury-induced regeneration the stromal niche, specified by Hedgehog pathway activity, supplies both proliferative and differentiative signals to the overlying epithelium. B. During the early stages of cancer formation genetic lesions with intrinsic proliferative effects in nascent tumor cells obviate the need for proliferative signals from the stromal niche. At this early stage, however, differentiation-promoting factors from the stromal niche are still able to restrain tumor growth/invasion. C. Loss of Hedgehog pathway activity specifying the stromal niche disrupts production of the differentiation-inducing factors, allowing unrestrained cancer invasion and progression.