Hyperglycaemia and aberrated insulin signalling stimulate tumour progression via induction of the extracellular matrix component hyaluronan

Abstract

Epidemiological studies have detected a higher incidence of various tumour entities in diabetic patients. However, the underlying mechanisms remain insufficiently understood. Glucose-derived pericellular and extracellular hyaluronan (HA) promotes tumour progression and development. In our study, we tested the hypothesis that a diabetic metabolic state, characterised by hyperglycaemia and concomitant aberrant insulin signalling, stimulates tumour progression via the induction of HA synthesis. In a streptozotocin-induced diabetic nude mouse tumour xenograft model, hyperglycaemia and lack of insulin caused an increased formation of tumour-associated HA-matrix, which in turn accelerated tumour progression and neoangiogenesis. This process was effectively attenuated by treatment with 4-methylumbelliferone, a pharmacological inhibitor of HA-synthesis. To define the mechanisms behind these in vivo observations, we investigated the impact of hyperglycaemia and insulin on the glucose metabolism in oesophageal squamous cell cancer cells (ESCC). Hyperglycaemia induced HA synthesis while insulin diminished HA production by directing glucose metabolites to glycolysis. Vice versa, inhibition of glycolysis, either by knockdown of the glycolytic key enzyme phosphofructokinase or by an experimental abrogation of insulin signalling (knockdown of the insulin receptor and long-term treatment with insulin) augmented HA synthesis. Consequently, these processes induced invasion, anchorage-independent growth and adhesion of ESCC to endothelial cells in vitro. Thus, the cellular shift in glucose usage from catabolism of glucose to anabolism of HA driven by hyperglycaemia and insulin resistance may represent an important link between diabetes and cancer progression. Hence, therapeutical inhibition of HA synthesis may represent a promising approach for tumour treatment in diabetic patients.

UDP-sugar accumulation drives hyaluronan synthesis in breast cancer

“…A recent study indicated that diabetic hyperglycaemia accelerates tumor growth in a mouse xenograft model in a hyaluronan dependent manner. Furthermore, in vitro experiments in the same paper indicate that the hyaluronan surplus depends on increased levels of glycolysis intermediates[27]. Western life style and obesity are associated with increased BMI.…”

Inhibition of the hyaluronan matrix enhances metabolic anticancer therapy by dichloroacetate in vitro and in vivo

“…What is the clinical significance documented (Table S5). In animal experiments, 4-MU was shown to attenuate tumour progression of, for example, oesophageal squamous cell carcinoma (ESCC) cells (Twarock et al, 2011;Twarock et al, 2017), hepatoma cells (Piccioni et al, 2015), bladder cancer cells (Morera et al, 2017), and prostate cancer cells (Lokeshwar et al, 2010). Moreover, it reduced metastatic spread of melanoma cells (Yoshihara et al, 2005) and chemotherapy resistance of pancreatic cancer cells (Nakazawa et al, 2006) and breast cancer cells (Chen & Bourguignon, 2014;Palyi-Krekk et al, 2007).…”

“…For further references, see also Table S6. Current research is aiming at identifying diseases and conditions in which 4-MU may present a valuable treatment option (Twarock et al, 2017).…”

“…As higher doses can also impair the synthesis of other glycosaminoglycans (unpublished data), we chose this dose as the highest concentration in our study. Based on the synergism calculation on growth reduction (Table S2) and our previous publications (Twarock et al, 2011;Twarock et al, 2017), we chose the 300-μM dose for further experiments.…”

“…In order to identify potential compounds that enhance the efficacy of dichloroacetate or other strategies aiming at the restoration of mitochondrial OXPHOS, we focused on the extracellular matrix (ECM) as it is a pivotal component of the tumour stroma by forming a supportive tumour micro-environment (Pickup, Mouw, & Weaver, 2014). Specifically, we investigated the role of the ECM component hyaluronan (HA) as its synthesis is closely coupled to glycolysis intermediates (Moretto et al, 2015;Tammi et al, 2011;Twarock et al, 2017) and its abundance in the vicinity of cancer cells is a hallmark of tumour development, which has been shown to support tumour growth and spread, metastasis, chemotherapy resistance, and antiapoptosis (Chanmee, Ontong, & Itano, 2016;Tammi et al, 2018).…”