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Deregulated Intestinal Stem and Progenitor Cells - Linking Obesity to Cancer

Review of “High-fat diet enhances stemness and tumorigenicity of intestinal progenitors” from Nature by Stuart P. Atkinson

Obesity has long been linked to the development of colorectal cancer (CRC) [1], but while calorie-restricted diets can modulate Lgr5+ intestinal stem cell (ISCs) function [2, 3], whether or not high-fat diets (HFDs) affect ISCs and promote tumorigenesis is less well known.

In order to fill this gap in knowledge, the laboratories of David M. Sabatini and Ömer H. Yilmaz have used in vivo analyses and in vitro intestinal organoid formation to assess the links between long-term HFD-induced obesity, intestinal stem/progenitor cells function, and tumor development.

Their new study suggests a pivotal role for peroxisome proliferator-activated receptor delta (PPAR-δ) in the promotion of self-renewal characteristics in intestinal stem/progenitor cells in response to high levels of fatty acids, thereby promoting colorectal cancer progression [4].

Initial analyses demonstrated that long-term (9-14 months) HFD led to obesity, increased ISC number and proliferation, and augmented intestinal regenerative capacity both in vitro (using intestinal organoids) and in vivo. Moreover, the organoid assay also suggested that the HFD enhanced the niche-independent growth of ISCs (expressing high levels of Lgr5) and intestinal progenitors (expressing low levels of Lgr5).

But what part of the HFD promotes these pro-tumorigenic effects and how do they function mechanistically? The authors discovered that diet supplementation with mixtures of fatty acids recapitulated the same effects as the HFD and also that these fatty acids induced organoid self-renewal via nuclear receptor peroxisome proliferator-activated receptor (PPAR)-δ mediated activation of a subset of β-catenin target genes in stem and progenitor cells.

But how does this all affect cancer development/progression? The study established that mice fed with an HFD displayed a greater incidence of spontaneous intestinal low-grade dysplastic lesions (adenomas) and carcinomas, perhaps due to the increased number and activity of ISCs. However, the authors noted that non-ISC progenitors fed under the HFD, or treated with a PPAR-δ-agonist, also formed organoids (normally only stem cells have this ability) suggesting intestinal progenitors may also drive tumorigenicity.

The study addressed this point employing a mouse model which allowed for the conditional knock out of the colorectal cancer-related tumor suppressor APC. Interestingly, after APC knockout under HFD conditions, progenitor cells displayed an increased ability to form adenomatous organoids in vitro and adenomas in vivo following cell transplantation into recipient colons.

The authors now hope to address whether PPAR-δ inhibition during an HFD would minimize tumor initiation and progression as hinted at in previous studies [5]. Furthermore, they hope that extended analysis of the in vitro intestinal organoid model system may uncover other druggable targets in stem/progenitor cells which may function synergistically with PPAR-δ inhibition.

References

  1. Calle EE and Kaaks R Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004;4:579-591.
  2. Yilmaz OH, Katajisto P, Lamming DW, et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 2012;486:490-495.
  3. Sato T, van Es JH, Snippert HJ, et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 2011;469:415-418.
  4. Beyaz S, Mana MD, Roper J, et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 2016;531:53-58.
  5. Neels JG and Grimaldi PA Physiological functions of peroxisome proliferator-activated receptor beta. Physiol Rev 2014;94:795-858.