Cancer metabolism: new validated targets for drug discovery

Abstract

Recent studies in cancer metabolism directly implicate catabolic fibroblasts as a new rich source of i) energy and ii) biomass, for the growth and survival of anabolic cancer cells. Conversely, anabolic cancer cells upregulate oxidative mitochondrial metabolism, to take advantage of the abundant fibroblast fuel supply. This simple model of "metabolic-symbiosis" has now been independently validated in several different types of human cancers, including breast, ovarian, and prostate tumors. Biomarkers of metabolic-symbiosis are excellent predictors of tumor recurrence, metastasis, and drug resistance, as well as poor patient survival. New pre-clinical models of metabolic-symbiosis have been generated and they genetically validate that catabolic fibroblasts promote tumor growth and metastasis. Over 30 different stable lines of catabolic fibroblasts and >10 different lines of anabolic cancer cells have been created and are well-characterized. For example, catabolic fibroblasts harboring ATG16L1 increase tumor cell metastasis by >11.5-fold, despite the fact that genetically identical cancer cells were used. Taken together, these studies provide >40 novel validated targets, for new drug discovery and anti-cancer therapy. Since anabolic cancer cells amplify their capacity for oxidative mitochondrial metabolism, we should consider therapeutically targeting mitochondrial biogenesis and OXPHOS in epithelial cancer cells. As metabolic-symbiosis promotes drug-resistance and may represent the escape mechanism during anti-angiogenic therapy, new drugs targeting metabolic-symbiosis may also be effective in cancer patients with recurrent and advanced metastatic disease.

Figure 1. Metabolic-Symbiosis in Human Cancer(s): New Therapeutic Targets

Two-Compartment Tumor Metabolism: Schematic Diagram. Catabolic stromal fibroblasts produce high-energy mitochondrial fuels, for cancer cells to use as substrates for OXPHOS and as biomass. Oncogenes (gain-of-function) and tumor suppressors (loss-of-function) both induce catabolism in adjacent fibroblasts, via ROS production (hydrogen peroxide) and the onset of oxidative stress.

Figure 2. Mitochondrial Activity Staining in Fresh Frozen Human Breast Cancer Tumor Tissue Sections

Note that epithelial cancer cell “nests” amplify their mitochondrial metabolism. In contrast, surrounding stromal fibroblasts show little or no functional mitochondrial staining, indicating that they show a shift towards glycolysis. COX, NADH, and SBH represent functional activity staining for mitochondrial complex IV, I, and III, respectively. Reproduced, with permission, from [58].

Figure 3. Visualizing Two-Compartment Tumor Metabolism, with Metabolic Marker Proteins: MCT4 and TOMM20

Human breast cancer samples (from primary tumors or lymph node metastases) were immuno-stained with antibodies directed against MCT4 (shown in RED) and TOMM20 (shown in BROWN). MCT4 is a marker of cellular stress, such as ROS production, glycolysis, and mitochondrial dysfunction, which reflects catabolic metabolism in cancer-associated fibroblasts. Conversely, TOMM20 is a marker of mitochondrial mass that has been shown to correlate with oxidative mitochondrial metabolism. Note that two distinct metabolic compartments (oxidative vs. glycolytic) co-exist, side-by-side, in human primary tumors. Virtually identical results were obtained with metastatic breast cancer lesions, within lymph node tissue. Insets are also shown at higher magnification. Reproduced, with permission, from [52].

Figure 4. Anti-Oxidants Halt Mitochondrial Biogenesis Selectively in Cancer Cells, But Not in Non-transformed Epithelial Cells

Epithelial cells (control versus H-Ras (G12V) transformed) were maintained (plus or minus NAC (10 mM)) and then subjected to immuno-staining with TOMM20, which is a well-established mitochondrial marker. Note that Ras-transformed cells, treated with NAC, show a significant decrease in mitochondrial mass. DAPI (blue nuclear staining) is also shown. Reproduced, with permission, from [56].