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Figure 1. A, the proposed model of tumor metabolism. Step 1, glucose and pyruvate reach the tumor-associated fibroblasts through the tumor-associated vasculature followed by absorption of glucose by GLUT1, which is expressed strongly () in the cellular membranes of cancer cells (o). Glucose absorption by stromal fibroblasts is much lower ( reduced uptake), as suggested by the lack of GLUT1 expression ( low levels; B, o). In contrast, endothelial cells are enriched with GLUT1, which enables them to absorb glucose directly from the blood. Step 2, in cancer cells, glucose is first transformed into pyruvate and subsequently to lactate through the intense activity of LDH5 (B, h). Pyruvate is unlikely to be used by cancer cell mitochondria (B, m) intensively, as PDH is suppressed (B, b) and PDK1 (inhibiting PDH activity) is overexpressed (B, d). Cancer cells may, therefore, have minimal requirements for oxygen so that oxygen use is reduced (). Step 3, the high concentrations of lactate in the cancer cell cytoplasm is rapidly extruded to the extracellular matrix through the intense activity of the MCT1 membrane monocarboxylate pump (B, k-m). This protects cancer cells from acidic death and results in acidification of the extracellular matrix. Lactate can diffuse into the circulation through blood vessels. Step 4, the high expression of MCT1 in stromal fibroblasts (B, l) results, under low pH matrix conditions, in intense absorption of lactate that is eventually used as a fuel to acquire energy after its oxidation back to pyruvate. This is suggested by the lack of LDH5 (B, h) and HIF (B, q) expression in stromal fibroblasts, the presence of LDH1 (B, f), the impressive lack of PDK1 (B, d), and the overexpression of PDH (B, b). Aerobic metabolism is, therefore, the main source of energy acquired by fibrobasts; thus, the oxygen diffused from the tumor-associated vessels is used mainly by the stroma and not by cancer cells. Blood vessels also share an enzymic/transported profile characteristic of aerobic metabolism, but unlike fibroblasts, endothelial cells do not express MCT1 (B, k), presumably reducing absorption of lactate and protecting themselves from acidic death. Step 5, excess pyruvate production within fibroblasts creates a gradient between cytoplasm and extracellular matrix, with MCT1 exporting pyruvate that can be used subsequently by cancer cells as a fuel, ending again in lactate production. B, PDH expression is strongly positive in normal intestinal mucosa (a; black arrows) and in tumor-associated stroma (b; yellow arrows), but it is absent from cancer cells (b; red arrows). PDK1 is weakly expressed in the normal mucosa (c; black arrows); it is absent from the tumor-associated stroma (d; red arrows), but it is strongly expressed in the cytoplasm of colorectal cancer cells (d; red arrows). LDH1 is strongly expressed in normal intestinal mucosa (e; black arrows) and in the tumor-associated stroma (e; yellow arrows), but its expression is variable in cancer cells (weak expression exhibited in e; red arrows). Lack of LDH5 expression is seen in normal intestinal mucosa (g; black arrows). Strong LDH5 expression is evident in cancer cells (red arrows) but not in the adjacent tumor-associated fibroblasts (h; yellow arrows). Strong basal and lateral membranous MCT1 expression is noted in normal intestinal mucosa (i and j; black arrows). MCT1 shows a strong membranous and cytoplasmic reactivity in colorectal tumor cells (k and m; red arrows). Strong expression is also noted in tumor-associated fibroblasts (l; yellow arrows). Intratumoral vessels were unreactive to MCT1 antibody (k; yellow arrows). GLUT1 is strongly expressed by cancer cells (o; red arrows); a weak expression is noted in colorectal mucosal cells (n; black arrows), but it is absent from the tumor-associated fibroblasts (o; yellow arrows). HIF1 is not detected in the normal intestinal mucosa (p; black arrows), but it is strongly expressed in colorectal cancer cells (q; red arrows); HIF1 is by and large absent from the tumor-associated fibroblasts (q; yellow arrows). Magnification, x100 (i and l) and x200 (a-h, j, k, and m-q).

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