Introduction: Tumor cells favor glycolysis even in the presence of normal oxygen partial pressures. This phenomenon termed the Warburg effect may be facilitated by the tumor-supporting stroma. The present study investigated the association between proteins associated with tumor metabolism; monocarboxylate transporter (MCT) 1, MCT 2, lactate dehydrogenase (LDH) 1 and LDH 5, the tumor microenvironment, and outcome in patients with colorectal cancer.
Methods: Patients who underwent elective, potentially curative surgery, and who were included in a previously constructed tissue microarray (TMA), were identified from a prospectively collected and maintained database of colorectal cancer resections at a single surgical unit from 1997-2007. Patients who underwent emergency or palliative surgery, with pre-existing inflammatory or auto-immune co-morbidity, or who underwent neoadjuvant chemoradiotherapy were excluded. Immunohistochemical assessment of MCT 1, MCT 2, LDH 1, and LDH 5 expression was performed using the weighted histoscore method. All antibodies were validated by western blotting and blocking experiments. Routine H&E staining and specific staining of tumor sections for CD3+, CD8+, CD45R0+, and FOXP3+ T cells was used to assess the tumor microenvironment including tumor stroma percentage (TSP). Patients were then stratified by a combination of TSP (≤50% or >50%) and expression of MCT 1, MCT 2, LDH 1, and LDH 5 (low or high) to give 4 groups for each protein in each intracellular location (membrane, cytoplasm and nucleus); low TSP and low protein expression, low TSP and high protein expression, high TSP and low protein expression, and high TSP and high protein expression. The relationship between a combination of TSP and markers of tumor metabolism, clinicopathological characteristics, local and systemic inflammatory responses, and cancer specific survival was examined using univariate and multivariate Cox regression
Results: 190 patients were included of which the majority were male (106, 56%), over 65 (115, 61%), with colonic (120, 63%) and node negative disease (103, 54%). 52 patients (27%) received adjuvant therapy. Mismatch repair deficiency was identified in 23 patients (13%). The median follow up of survivors was 132 months (range 74-194) with 63 cancer associated deaths and 51 non-cancer deaths. At univariate analysis there was a significant association between cancer specific survival and TNM stage (HR 2.26, 95% CI 1.50-3.41, p<0.001), venous invasion (HR 2.53, 95% CI 1.62-3.95, p<0.001), margin involvement (HR 2.44, 95% CI 1.12-5.31, p = 0.025), peritoneal involvement (HR 2.11, 95% CI 1.34-3.30, p = 0.001), tumor perforation (HR 7.79, 95% CI 2.78-21.85, p<0.001), modified Glasgow Prognostic Score (mGSP) (HR 1.68, 95% CI 1.25-2.26, p = 0.001), neutrophil platelet score (NPS) (HR 1.91, 95% CI 1.23-2.98, p = 0.004), Klintrup-Makinen grade (HR 2.36, 95% CI 1.34-4.14, p = 0.003), and TSP (HR 2.01, 95% CI 1.23-3.29, p = 0.005). At univariate analysis there was a significant association between cancer specific survival and the combination of TSP and membrane expression of MCT 1 (HR 1.49, 95% CI 1.16-1.91, p = 0.002), TSP and cytoplasmic expression of MCT 1 (HR 1.44, 95% CI 1.13-1.83, p = 0.003), MCT 2 (HR 1.33, 95% CI 1.04-1.70, p = 0.021), LDH 1 (HR 1.53, 95% CI 1.18-1.98, p = 0.001), LDH 5 (HR 1.60, 95% CI 1.21-2.11, p = 0.001), TSP and nuclear expression of MCT 1 (HR 1.47, 95% CI 1.17-1.85, p = 0.003), MCT 2 (HR 1.49, 95% CI 1.16-1.90, p<0.001), LDH 1 (HR 1.36, 95% CI 1.07-1.74, p = 0.037), and LDH 5 (HR 1.57, 95% CI 1.20-2.05, p<0.001). At multivariate analysis the combination of TSP and nuclear MCT 2 expression (HR 1.61, 95% CI 1.13-2.31, p = 0.009), venous invasion (HR 3.51, 95% CI 1.55-7.95, p = 0.003), and tumor perforation (HR 25.31, 95% CI 2.75-233.11, p = 0.004), remained independently associated with cancer specific survival. The combination of TSP and nuclear MCT 2 expression was significantly associated with tumor differentiation (p = 0.017), budding (p<0.001), and CD3+ lymphocyte cancer cell nest density (p = 0.045).
Conclusions: In patients undergoing surgery for colorectal cancer, the combination of tumor stroma percentage and nuclear MCT 2 expression is prognostically significant independent of stage at presentation. Furthermore the combination of tumor stroma percentage and nuclear MCT 2 expression was associated with tumor budding. Metabolic interactions between the stroma and tumor cell may be an important method by which invasion and metastases occur.
Citation Format: Stephen T. McSorley, Jennifer Clark, Hester C. van Wyk, Paul G. Horgan, Donald C. McMillan, Joanne Edwards, James H. Park. The association between markers of tumor cell metabolism, the tumor microenvironment, and outcomes in patients with colorectal cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A130.
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