Remodelling of colorectal cancer cell signalling by microbiota and immunity in diabetes.

Obesity is the strongest known risk factor to develop type 2 diabetes (T2D) and both share a state of chronic, diffuse and low-grade inflammation, impaired immune responses and alterations in the composition and function of the microbiome. Notably, these hallmarks are shared with colorectal cancer (CRC), which is epidemiologically associated to obesity and T2D. Gut barrier damages in T2D destabilize the microbiome that metabolizes the diet and modulates the host immune response triggering inflammatory and proliferative pathways. In this review, we discuss the pathways altered by defects in the immune response and microbiota that may link T2D to CRC development. Stressed adipocytes, metabolic incongruity in blood and gut barrier failure with dysbiosis cooperate to establish imbalances between immune innate and adaptive cells and cytokines such as interleukin 6 (IL6) or TNFA that define low-grade diffuse inflammation in T2D. Inflammation drives tissue repair through proliferation and migration (critical mechanisms for tumourigenesis) and under physiological conditions feeds anti-inflammatory cytokine production to resolve the process. The disproportion in pro- vs anti-inflammatory cells and cytokines imposed by T2D will impact the tumour micro- and macro-environment, favouring tumour proliferation, angiogenesis and decreased immune responses. Complex bidirectional relationships between the metabolic environment of T2D, gut microbiota, and immune dysfunctions may favour tumour cell demands and will define the outcome. Animal models developed to study the relationships between T2D and CRC in the context of microbiota and immune system are discussed.

Metabolic and hormonal remodeling of colorectal cancer cell signalling by diabetes.

The existence of molecular links that facilitate colorectal cancer (CRC) development in the population with type 2 diabetes (T2D) is supported by substantial epidemiological evidence. This review summarizes how the systemic, metabolic and hormonal imbalances from T2D alter CRC cell metabolism, signalling and gene expression as well as their reciprocal meshing, with an overview of CRC molecular subtypes and animal models to study the diabetes-CRC cancer links. Metabolic and growth factor checkpoints ensure a physiological cell proliferation rate compatible with limited nutrient supply. Hyperinsulinaemia and hyperleptinaemia in prediabetes and excess circulating glucose and lipids in T2D overcome formidable barriers for tumour development. Increased nutrient availability favours metabolic reprogramming, alters signalling and generates mutations and epigenetic modifications through increased reactive oxygen species and oncometabolites. The reciprocal control between metabolism and hormone signalling is lost in diabetes. Excess adipose tissue at the origin of T2D unbalances adipokine (leptin/adiponectin) secretion ratios and function and disrupts the insulin/IGF axes. Leptin/adiponectin imbalances in T2D are believed to promote proliferation and invasion of CRC cancer cells and contribute to inflammation, an important component of CRC tumourigenesis. Disruption of the insulin/IGF axes in T2D targets systemic and CRC cell metabolic reprogramming, survival and proliferation. Future research to clarify the molecular diabetes-CRC links will help to prevent CRC and reduce its incidence in the diabetic population and must guide therapeutic decisions.

EGF promotes neuroendocrine-like differentiation of prostate cancer cells in the presence of LY294002 through increased ErbB2 expression independent of the phosphatidylinositol 3-kinase-AKT pathway.

An increased neuroendocrine (NE) cell population in prostate cancer is associated with more aggressive disease and recurrence after androgen-deprivation therapy, although the mechanism responsible is unknown. In this study, we report that the treatment of LNCaP cells with epidermal growth factor (EGF) in the presence of LY294002, an inhibitor of the phosphoinositol 3'-kinase (PI3K)-AKT pathway, induced an increase of levels and activity of ErbB2. Under these conditions, we also observed cell survival and NE differentiation. When we treated with wortmannin, another PI3K inhibitor, or we knocked down PI3K or AKT isoforms in the presence of EGF, ErbB2 up-regulation was not observed, suggesting that the increase of ErbB2 induced by EGF plus LY294002 is not mediated by the PI3K-Akt pathway. Other targets of LY294002 were also discounted. We also show that ErbB2 up-regulation is directly involved in neuroendocine differentiation but not in cell survival as ErbB2 levels increased in parallel with NE differentiation marker levels, whereas ErbB2 knockdown reduced them; other NE differentiation inducers also increased the ErbB2 levels and the immunohistochemical analysis of prostate cancer samples showed colocalization of ErbB2 and chromogranin A. We found that, in LNCaP cells, EGF in combination with LY294002 increased ErbB2 levels by a PI3K/AKT-independent mechanism and that this increase was associated with the acquisition of a NE phenotype. These results suggest that is worth reconsidering ErbB2 as a drug target in prostate cancer and this should be kept in mind when designing new clinical schedules for the treatment of this disease.

EGF prevents the neuroendocrine differentiation of LNCaP cells induced by serum deprivation: the modulator role of PI3K/Akt.

The primary focus of this investigation was to study the relationship between neuroendocrine (NE) differentiation and epidermal growth factor (EGF) because both have been implicated in the progression of prostate cancer. For this purpose, we used gefitinib and trastuzumab, which are inhibitors of EGF receptor (EGFR) and ErbB2, respectively. EGF prevents NE differentiation induced by androgen depletion. This effect is prevented by gefitinib, which blocks the activation of EGFR and ErbB2, stimulation of mitogen-activated protein kinase (MAPK), and cell proliferation induced by EGF. Conversely, trastuzumab does not inhibit the effect of EGF on EGFR phosphorylation, MAPK activity, cell proliferation, and NE differentiation, although it reduces ErbB2 levels specifically, suggesting that ErbB2 is not necessary to inhibit NE differentiation. Prevention of NE differentiation by EGF is mediated by a MAPK-dependent mechanism and requires constitutive Akt activation. The abrogation of the PI3K/Akt pathway changes the role of EGF from inhibitor to inductor of NE differentiation. We show that EGFR tyrosine kinase, MAPK, and PI3K inhibitors inhibit the cell proliferation stimulated by EGF but induce the acquisition of NE phenotype. Altogether, the present data should be borne in mind when designing new clinical schedules for the treatment of prostate cancer, including the use of ErbB receptors and associated signaling pathway inhibitors.