The association between markers of tumor cell metabolism, the tumor microenvironment and outcomes in patients with colorectal cancer

Tumor cell anaerobic metabolism has been reported to be a prognostic factor in colorectal cancer. The present study investigated the association between monocarboxylate transporter (MCT) 1, MCT 2, lactate dehydrogenase (LDH) 1 and LDH 5, the tumor microenvironment, and outcome in patients with colorectal cancer. A cohort of 150 patients with stage I‐III CRC were utilised to assess tumor cell expression of MCT‐1, MCT‐2, LDH‐1 and LDH5 by immunohistochemistry. Expression levels were dichotomised and associations with tumor factors, the tumor microenvironment and survival analysed. Nuclear LDH‐5 associates with poor prognosis (HR 1.68 95% CI 0.99‐2.84, p=0.050) and trends towards increased tumor stroma percentage (TSP, p=0.125). Cytoplasmic MCT‐2 also trends towards increased TSP (p=0.081). When combined into a single score; nuclear LDH‐5+TSP significantly associated with decreased survival independent of stage (HR 2.61 95% CI 1.27‐5.35, p=0.009), increased tumor budding (p=0.002) and decreased stromal T‐lymphocytes (p=0.014). Similarly, cytoplasmic MCT‐2+TSP significantly associated with decreased survival (HR 2.32 95% CI 1.31‐4.11, p=0.003), decreased necrosis (p=0.039), and increased tumor budding (p=0.004). The present study reports that the combination of TSP and nuclear LDH‐5 was significantly associated with survival, increased tumor budding, and decreased stromal T‐lymphocytes. This supports the hypothesis that increased stromal invasion promotes tumor progression via modulation of tumor metabolism. Moreover, MCT‐2 and LDH‐5 may provide promising therapeutic targets for patients with stromal‐rich CRC.

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