Proliferating fibroblasts at the invading tumour edge of colorectal adenocarcinomas are associated with endogenous markers of hypoxia, acidity, and oxidative stress

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Abstract
Background: Stroma frequently forms at sites of active tumour invasion, and may be important for tumour growth and progression. The term “stromatogenesis” is used to describe this unique process that involves host peritumorous fibroblasts and is very different to reactive fibrosis. Aims/Methods: To investigate the activation status of host fibroblasts at the invading tumour edge, assessed as MIB1 proliferation index and thymidine phosphorylase (TP) expression. Results were related to vascular density and certain properties of invading cancer cells—MIB1 proliferation activity, TP expression, expression of endogenous markers of hypoxia (hypoxia inducible factor-1α; HIF1α) and acidity (lactate dehydrogenase-5; LDH5). Standard immunohistochemical techniques were applied to 150 colorectal adenocarcinomas. Results: Normal fibroblasts at the tumour edge had a median MIB1 index of 2%—significantly higher than normal submucosal fibroblasts (0.3%) and significantly lower than cancer cells (40%). Normal peritumorous fibroblasts with a proliferation rate above the median strongly expressed TP and were supported by an increased vascular network. Cancer cells close to these fibroblasts had a high MIB1 proliferative index, high HIF1α and LDH5 reactivity, and a clear trend to extramural extension. All associations were significant. Conclusions: These results suggest that activated fibroblastic status at the invading tumour front sets the stage for stromatogenesis and new blood vessel formation, facilitating deep transmural invasion in colorectal adenocarcinomas. This complicity of peritumorous fibroblasts in the overall aggressiveness/invasive and metastatic ability of colorectal tumours, occurring within the framework of cancer–stromal cell interactions, is probably favoured by the altered microenvironmental conditions of hypoxia and acidity.

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