Molecular Pathways: Trafficking of Metabolic Resources in the Tumor Microenvironment

摘要

Abstract A model of tumor metabolism is proposed that describes how the complementary metabolic functions of the local stroma and the tumor cells contribute to cancer progression. Cancer cells alter the metabolism of cancer-associated fibroblasts to obtain lactate and amino acids, which are utilized for energy production, rapid growth, and resistance to chemotherapy drugs. Cancer cells use glutamine supplied by cancer-associated fibroblasts to replenish tricarboxylic acid cycle intermediates and as a nitrogen source for nudeotide synthesis. Moreover, adipocytes in the microenviron-ment attract cancer cells through the secretion of inflammatory cytokines and proteases. The cancer cells then induce metabolic changes in the adipocytes to acquire free fatty acids that are oxidized by cancer cells to generate energy for proliferation. Increasing knowledge about the metabolic symbiosis within the tumor has led to novel therapeutic strategies designed to restrict metabolic adaptation, including inhibiting lactate transporters and repurposing antidiabetic drugs (thiazolidinediones, metfor-min). Background The identification of cancer as a genetic disease, compellingly established by the detection of genomic derangements within malignant cells, led researchers to focus on alterations in tumor suppressor genes and oncogenes. However, in the last decade, our genetic view has been expanded by the observation that tumors are thriving organs with multiple cell types within a distinctive extracellular matrix (ECM), and that all these components can affect tumor progression and response to therapies. This view has added significant complexity to the study of human tumors, as it takes into consideration the effects of fibroblasts, mesothelial cells, immune cells, adipocytes, and endothelial cells on tumor growth. During transformation and metastasis, cancer cells recruit these cell types to surround themselves with a supportive tumor micro-environment (TME). Over time, the tumor and the adjacent cells coevolve and even metastasize together (1). Stromal cells are recruited by paracrine growth factors (e.g., PDGF and VEGF] secreted by cancer cells and then, in turn, secrete cytokines (e.g., HGF, TGF|3, and CCL5; refs. 2-4), which accelerate the aggressiveness of cancer cells.