In situ Metabolic Profiling of Ovarian Cancer Tumor Xenografts: A Digital Pathology Approach

Abstract

Metabolic profiling of cancer is a rising interest in the field of biomarker development. One bottleneck of its clinical exploitation, however, is the lack of simple and quantitative techniques that enable to capture the key metabolic traits of tumor from archival samples. In fact, liquid chromatography associated with mass spectrometry is the gold-standard technique for the study of tumor metabolism because it has high levels of accuracy and precision. However, it requires freshly frozen samples, which are difficult to collect in large multi-centric clinical studies. For this reason, we propose here to investigate a set of established metabolism-associated protein markers by exploiting immunohistochemistry coupled with digital pathology. As case study, we quantified expression of MCT1, MCT4, GLS, PHGDH, FAS, and ACC in 17 patient-derived ovarian cancer xenografts and correlated it with survival. Among these markers, the glycolysis-associated marker MCT4 was negatively associated with survival of mice. The algorithm enabling a quantitative analysis of these metabolism-associated markers is an innovative research tool that can be exported to large sets of clinical samples and can remove the variability of individual interpretation of immunohistochemistry results.

Energy Substrate Transporters in High-Grade Ovarian Cancer: Gene Expression and Clinical Implications

“…Therefore, the MCT4-dependent mechanisms that contribute to EOC relapse need to be elucidated, because this transporter can potentially be used in targeted therapy in drug-resistant OC. The study conducted on mice with OC revealed that elevated MCT4 concentration yielded increased mouse mortality [ 50 ]. Interestingly, enhanced expression of MCT4 was observed in tumor stroma, especially in cancer-associated fibroblasts in breast cancer, whereas MCT1 was preferentially expressed in epithelial cancer cells and contributed to the influx of lactate to cancer cells.…”

PGK1 Is a Key Target for Anti-Glycolytic Therapy of Ovarian Cancer: Based on the Comprehensive Analysis of Glycolysis-Related Genes

“…In addition, high PKM2 expression was closely associated with poor PFS, and correlated with short OS in platinum-treated epithelial ovarian cancer (23)(24)(25). For metabolite transporters, the expression level of GLUTs was not a prognostic factor of ovarian cancer, however, MCT4 negatively correlated with survival of mice confirmed based on in situ metabolic profiling of ovarian cancer tumor xenografts (26,27). However, the prognostic value of other indicators in ovarian cancer has not been extensively explored.…”

Expression and prognostic value of TRPM7 in canine mammary tumours

“…Aperio Cytoplasm V2 algorithm was used to analyse cytoplasmic positivity of TRPM7 expression, based on criteria for TRPM7 in human breast cancer. 29 , 30 The positive expression of TRPM7 in cytoplasm was quantitatively assessed, for each sample in 10 randomly selected high‐power fields (400×), as follows: 0 (negative), +1 (weakly positive), +2 (moderately positive) and + 3 (strongly positive). Staining intensities for TRPM7 expression ranged from 0 to 3 and were correlated with conventional manual scoring methods.…”