High fat diet and stem cells: Linking diet to intestinal tumor formation

In recent years, diet has been increasingly recognized as a significant modifiable risk factor for cancer initiation and progression in multiple organ systems.¹ The pathophysiological effects of diet have garnered attention among the scientific community in response to the increasing worldwide adoption of the Western diet and accompanying rise in obesity rates. Indeed, epidemiological studies have shown that obesity is associated with elevated risk of many types of cancer, particularly those of the gastrointestinal tract.² A main driver in how diet contributes to cancer incidence is by changing the biology of long-lived adult stem cells. Such adult stem cells balance self-renewal divisions (divisions that generate stem cells) and differentiation divisions (divisions that generate non-stem cell progenitors) in response to multiple environmental inputs like diet to maintain tissue homeostasis. Moreover, adult stem cells in many tissues have been implicated as the cells that accumulate the initial mutations that ultimately beget cancers.^1,3 This paradigm has been best illustrated in the intestine, where Lgr5+ intestinal stem cells (ISCs) initiate and serve as the cells-of-origin for colorectal cancer.⁴ Although pro-obesity diets and obesity predispose to intestinal cancers, how they alter the biology and vulnerability of intestinal stem and progenitor cells to form tumors is uncertain.

We recently reported that in the intestine a long-term high-fat diet (HFD) enhances the tumor-initiating potential of ISCs and progenitor cells of the intestinal crypt, highlighting a prominent link between HFD-induced obesity and intestinal tumorigenesis.⁵ In mice, exposure to a HFD for 9–14 months resulted in many intestinal adaptations: 1) Intestinal villi (finger-like projections that house the differentiated cells of the intestine) became shorter, while intestinal crypts (tube-like invaginations that house the intestinal stem and progenitor cells) became hyperplastic; 2) ISC numbers were expanded, while the numbers of their adjacent Paneth niche cells were diminished; 3) Functionally, ISCs were less dependent on Paneth cells for initiating organoids (mini-intestines in cultures); and 4) Non-stem cell progenitors in a HFD acquired stem cell attributes, namely the capacity to form intestinal organoids. Lastly, fatty acid constituents of the HFD (e.g. palmitic acid or oleic acid) recapitulated many aspects of the HFD in the organoid assay, such as augmenting the frequency and niche independent growth of ISCs, indicating that dietary components of the HFD drive many of its effects.

From a mechanistic point-of-view as depicted in Figure 1, we identified PPAR-delta, a nuclear receptor that senses fatty acid derivatives, as the key mediator of the HFD effects in the intestine. Interestingly, we found that PPAR-delta was both sufficient and necessary for the HFD intestinal phenotype. For instance, synthetic activation of PPAR-delta with a small molecule ligand mimicked both the in vivo and in vitro impact of a HFD and fatty acid treatment, reduced the reliance of ISCs for niche cells in organoid formation, and endowed non-stem cell progenitors with stemness. Also, loss of PPAR-delta abrogated the fatty acid-driven self-renewal of intestinal organoids. Collectively, these data suggest that PPAR-delta is both necessary and sufficient for mediating the effects of a HFD in the intestine.

Figure 1.

A model for the effects of high fat diet (HFD) on intestinal stem and progenitor cell biology and tumorigenesis. HFD leads to crypt structural changes that include shorter villi and deeper crypts. Fatty acids induce PPAR-delta activation in intestinal stem cells (ISCs) (green) and progenitors (yellow). A PPAR-delta program initiates enhanced regenerative function and niche independence in ISCs, as indicated by increased ISC numbers, reduced Paneth cell (purple) numbers, and acquisition of stem-like properties in progenitors (yellow-green) such as organoid forming capacity. By enhancing ISC numbers and endowing progenitors with stemness, which together increase the pool of cells capable of undergoing oncogenic transformation, a HFD augments the incidence of tumorigenesis in the intestinal crypt.

Part of the mechanism of how PPAR-delta signaling augments ISC and progenitor function is by engaging a β-catenin program, a developmental pathway essential for intestinal homeostasis (Figure 1). We discovered that β-catenin target genes Jag1 and Jag2 (both ligands for Notch signaling) were robustly induced by HFD-activated PPAR-delta signaling in ISCs and progenitors. Normally, such Notch ligands are elaborated by Paneth cells, which elicit Notch signaling in adjacent ISCs. However, in a HFD, proximate ISCs or progenitors may serve as an alternate source of Notch ligands for ISCs that are not juxtaposed to Paneth cells, endowing ISCs with the ability to uncouple from their Paneth cell niche in vivo and acquire niche independence in the organoid assay.

An important question is how does HFD-induced PPAR-delta activity impact tumor initiation. First, we observed that HFD-fed mice developed more spontaneous intestinal low-grade adenomas and carcinomas than standard diet-fed mice. Second, we demonstrated that enforced PPAR-delta signaling not only enabled non-stem cell progenitors to form organoids, but also endowed them with the potential to initiate tumors in vivo. If many tumors normally arise from the oncogenic transformation of pre-existing stem cells, a HFD might raise tumor incidence in the intestine by increasing the stem cell pool. Another possibility suggested by our results is that a diet-induced PPAR-delta program also enhances the susceptibility of non-stem cells (i.e. progenitors) to undergo oncogenic transformation, leading to the generation of a larger, more diverse pool of cells capable of initiating tumors in the HFD state (Figure 1).⁵ Possessing more stem cells or non-stem cells that can undergo transformation may play a potential role in how HFD-induced obesity increases cancer incidence.¹

Although a HFD dramatically alters the biology of stem and progenitor cells in the intestine, it will be important to ascertain how reversible these changes are in the post-obese state. It will thus be imperative to investigate the stability of chromatin and epigenetic changes evoked by a HFD and how they influence ISC and progenitor function. Such insight may have consequences for dieters and their future risk of developing intestinal cancer. Another important question raised by our findings is how generalizable these changes that occur in a HFD are to other dietary and genetic models of obesity. Similarities and difference in how the intestine adapts to diverse paradigms of obesity may reveal biomarkers or mechanistic clues into how diverse nutrients like fatty acids or carbohydrates, or the physiologic responses elicited by them, drive intestinal tumorigenesis in obesity. Lastly, it will be important to understand whether diet-activated PPAR-delta targets can stratify obese patients in terms of cancer risk or serve as therapeutic targets for intestinal cancers that arise in the obese setting.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.