Dietary and metabolic control of stem cell function in physiology and cancer

Abstract

Organismal diet has a profound impact on tissue homeostasis and health in mammals. Adult stem cells are a keystone of tissue homeostasis that alters tissue composition by balancing self-renewal and differentiation divisions. Because somatic stem cells may respond to shifts in organismal physiology to orchestrate tissue remodeling and some cancers are understood to arise from transformed stem cells, there is a likely possibility that organismal diet, stem cell function, and cancer initiation are interconnected. Here we will explore the emerging effects of diet on nutrient-sensing pathways active in mammalian tissue stem cells and their relevance to normal and cancerous growth.

Figure 1. Dietary regulation of stem cells in tissue homeostasis

A. Intrinsic (dark green) and extrinsic (orange) diet-sensing mechanisms integrate diet-induced physiology with tissue homeostasis. Stem cells (blue) and their niche (green) sense physiologic cues such as hormones, growth factors, and nutrients to dynamically alter the production of differentiated cells (pink). B. Calorie restriction boosts regeneration in diverse tissues by increasing stem cell numbers and function. Niche-derived signals mediate some of the response of calorie restriction on stem cells. C. Diet-induced obesity is associated with an abundance of nutrients, growth factors, and hormones that eventually leads to physiologic disequilibrium, including insulin resistance, diabetes, and metabolic syndrome. This state reduces tissue repair, in part due to dysfunction of stem cells, their niche, or both.

Figure 2. Diet- sensing pathways in stem cells

Growth factor binding to receptor tyrosine kinases activates PI3K (phosphatidylinositol 3-kinase) and PTEN suppresses signaling through this pathway. PI3K and mTORC2 activate AKT, which regulates mTORC1 activity by inhibition of the TSC1/2 complex. Independently, the Rag-GTPases control mTORC1 activity in response to nutrients, such as amino acids and glucose, at the lysosome surface. Multiple pathways downstream of active mTORC1 control anabolic processes, including protein and lipid synthesis and inhibit catabolic processes like autophagy. S6 kinase 1 (S6K1) regulates protein synthesis and ribosome biogenesis and 4E-BP1 regulates cap-dependent protein translation. Deletion of PTEN or TSC1 leads to the activation of mTORC1 and to stem cell depletion. Treatment with mTORC1 inhibitor, rapamycin, restores loss of stem cell function. The energy sensor AMPK becomes activated in response to glucose starvation and relative increases in the ratio of AMP and ADP to ATP levels. AMPK is phosphorylated and activated in an AMP dependent manner by the upstream master kinase LKB1 and in turn negatively regulates mTORC1 to promote catabolic, energy producing processes such as autophagy and fatty acid oxidation. Another intracellular sensor, SIRT1, becomes activated in response to relative increases in the ratio of NAD+ to NADH to regulate the activity of FOXO transcription factors. FOXO family members control expression of genes involved in oxidative stress, cell death, cell cycle control and metabolism, which are important for stem cell maintenance.

Figure 3. The PI3K- mTOR axis in the HSCs and leukemia initiation

The PI3K-mTOR pathway and possible mechanism of HSC depletion and leukemia initiation. mTOR kinase nucleates two complexes: mTORC1 and mTORC2. mTORC2 is upstream of mTORC1 and activates AKT, which in turn induces downstream mTORC1 signaling. Deletion of PTEN leads to hyperactivation of AKT and inactivation of the TSC1/2 complex to activate mTORC1. Chronic mTORC1 signaling leads to the induction of tumor suppressor genes, such as p16^INK4a, p19^ARF, and p53, in stem cells. Treatment with rapamycin rescues this response in stem cells, restoring normal function. Although PTEN is required for the maintenance of HSCs, its loss gives rise to leukemia-initiating cells (or cells capable of transferring acute leukemia to recipient mice). Secondary mutations that inactivate the tumor repressive response in PTEN-deleted HSCs are likely required for leukemogenesis. Deletion of Rictor or Raptor, essential components of mTORC1 and mTORC2, respectively, or administration of rapamycin delay the decline in HSCs and the generation of leukemia with PTEN deficiency.

Figure 4. Diet and Cancer Initiation

A. In tissues that follow a stem cell paradigm, stem cells (red) acquire early oncogenic events (red arrow) that lead to transformation and tumor formation. B. Calorie restriction augments stem cell numbers and function in diverse tissues and is proposed to have anti-tumor initiation and growth effects. If stem cell numbers increase with calorie restriction and they undergo some of the early changes that give rise to tumors, calorie restriction may potentially increase tumor incidence. It is possible that autonomous and non-autonomous protective mechanisms are activated in stem cells with calorie restriction, which neutralize the effects of a larger, more robust stem cell pool. Another possibility may be that the anti-growth effects of calorie restriction on tumor growth mask its effects on initiation. Tumors arising in calorie restriction may remain below detection threshold because they are small in size. C. Diet-induced obesity has untoward effects on tissue repair and cancer incidence. Although stem cell numbers can decrease with chronic obesity, the susceptibility of differentiated cells to undergo transformation can also increase as has been noted to occur with inflammation. In this case, early oncogenic events can occur in stem cells and differentiated cells, effectively increasing the pool of cells that can undergo early transformation. Surplus growth factors, nutrients, and hormones, then drive tumor progression and growth.