Organ-Specific Cancer Metabolism and Its Potential for Therapy

Abstract

KEYWORDS:Cancer metabolism, metabolic therapy, tissue specific metabolism, genetic drivers, epigenetic drivers, microenvironment, Warburg effect, reverse Warburg effect, mixed Warburg effect, triple-negative breast cancer, estrogen receptor positive breast cancer; prostate cancer, liver cancer, gluconeogenesis, fatty acid metabolism, glucose metabolism, glutamine metabolism, serine metabolism, metabolic normalization, metabolic depletion ABSTRACTTargeting the metabolism of cancer cells has the potential to lead to major advances in tumor therapy. Numerous promising metabolic drug targets have been identified. Yet, it has emerged that there is no singular metabolism that defines the oncogenic state of the cell. Rather, the metabolism of cancer cells is a function of the requirements of a tumor. Hence, the tissue of origin, the (epi)genetic drivers, aberrant signaling, and the microenvironment all together define these metabolic requirements. In this chapter we discuss in light of (epi)genetic, signaling, and environmental factors the diversity in cancer metabolism based on triple-negative and estrogen receptor positive breast cancer, early and late stage prostate cancer, and liver cancer. These types of cancer all display distinct and partially opposing metabolic behaviors (e.g. Warburg versus reverse Warburg metabolism). Yet, for each of the cancers their distinct metabolism supports the oncogenic phenotype. Finally, we will assess the therapeutic potential of metabolism based on the concepts of metabolic normalization and metabolic depletion.

Macrophage Metabolism As Therapeutic Target for Cancer, Atherosclerosis, and Obesity

“…Cancer cells have, as a consequence of their highly proliferative potential, a metabolic signature that is notably different compared to nonmalignant cells. Several drugs that specifically target the metabolic pathways of cancer cells are in clinical trials (65, 66). However, in other inflammatory diseases, such as obesity and atherosclerosis, macrophages are highly involved in disease progression.…”

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

“…The importance of OXPHOS in cancer metabolism has been underappreciated despite evidence that mitochondria contribute to efficient ATP production in a variety of cancer cell lines (11,12). On the basis of the observation that breast cancer cells produce 80% of their ATP via mitochondrial-dependent metabolism, the concept of "oxidative tumors" has been introduced to describe ATP production by OXPHOS from glucose, fatty acids, or glutamine oxidation (13)(14)(15). In addition, maintenance of mitochondrial membrane potential by the electron transport chain is required to support the proliferation of cancer cells (16).…”

“…Cancer cells can display distinct metabolic features that are characteristic of the tissue of origin (13). Indeed, lung, liver, colorectal cancers, and leukemias rely heavily on glycolysis; whereas, lymphomas, melanomas, and glioblastomas are characterized as oxidative tumors ( …”

“…During transformation to early lesions, prostate cancer cells progressively switch toward OXPHOS-dependent metabolism (47). Interestingly, prostate cancer cells prioritize glycolytic metabolism during late stages of cancer progression, rendering them sensitive to 2-DG (13,(48)(49)(50)(51)(52)(53)(54). Thus, prostate cancer cells exhibit a mixed phenotype, where both glycolysis and OXPHOS are required for energy metabolism at different stage of disease progression (Table 1; ref.…”

“…Thus, prostate cancer cells exhibit a mixed phenotype, where both glycolysis and OXPHOS are required for energy metabolism at different stage of disease progression (Table 1; ref. 13). Glycolysis and OXPHOS may be considered complementary strategies that afford cancer cells maximum metabolic flexibility to deal with changes in nutrient supply, the biosynthetic/energy demands of the cell, and the immediate tumor microenvironment.…”