PerspectiveCancer Metabolism

The nutrient environment affects therapy

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Science  01 Jun 2018:
Vol. 360, Issue 6392, pp. 962-963
DOI: 10.1126/science.aar5986

Understanding the molecular basis of cancer has led to a revolution in how cancers are classified and treated. Subsets of patients benefit from precision-medicine drugs that target growth-promoting signaling networks, but not all cancer patients respond to these approaches (1). Precision medicine is largely built on the assumption that cancer cell–intrinsic factors, such as genetic mutations or epigenetic identity, determine which pathways and processes are required in cells and thus response to therapies. However, in many cases, the presence of particular genetic lesions is insufficient to identify patients that will respond to a drug (1). For instance, standard cell culture models have not identified the subsets of cancer patients that respond to most conventional chemotherapies (1). Nevertheless, these chemotherapy drugs remain standard of care for many cancers and, in some cases, contribute to curative regimens. Emerging data suggest that beyond cell-intrinsic factors, nutrient availability in the tumor microenvironment can also influence drug response. This highlights the importance of understanding the microenvironmental factors that dictate which cellular processes are essential for disease progression and ultimately how tumors respond to treatments that target these processes.

The success of conventional chemotherapy to treat patients with cancer argues that drugs that target cell metabolism and proliferative machinery, such as antimetabolite chemotherapy, can be effective. Recent efforts to target cancer metabolism have focused on how different cell-intrinsic factors such as oncogenic mutations rewire metabolism to require cells to use specific metabolic pathways and nutrients for growth and survival (2). There have been clinical successes from this approach, such as targeting mutant isocitrate dehydrogenases. However, the development of drugs that target enzymes in core metabolic pathways, such as those that metabolize glucose, has been challenging. Even though profound metabolic alterations are observed broadly in cancer, an inability to match the right patients with specific drugs has limited therapeutic development of new molecules that target metabolism.

Experiments in microorganisms have demonstrated that gene function and essentiality for proliferation and survival is largely environment dependent (3). That is, the availability of nutrients in the environment can affect whether microorganisms require certain genes to thrive. By extension, the tumor microenvironment may alter the essentiality of pathways in cancer cells and influence sensitivity to drugs ranging from classic chemotherapies to new, targeted agents (see the figure). Recent studies have demonstrated that microenvironmental factors have a profound influence on cancer cell metabolism and sensitivity to drugs that target metabolism. For example, biochemical analysis of both mouse and human tumors revealed different nutrient preferences for lung and brain tumors in vivo compared with cancer cells cultured from these tumors. In cultured lung and brain cancer cells, glutamine is used as a primary carbon source for metabolic pathways needed to synthesize macromolecules for growth, whereas glutamine catabolism can be less important in tumors formed from the same cells in mice (2). Furthermore, genetic screens of human cells in culture and in xenograft tumors have yielded discordant results with respect to metabolic gene essentiality (4), lending further support to the idea that cancer cells require different metabolic processes, depending on their microenvironment. The microenvironment can also affect drug response. For example, inhibitors of the enzyme glutaminase slow the proliferation of most cancer cells in culture, but this has not been predictive of tumor response to glutaminase inhibitors in either patients or mouse cancer models (2). Similarly, drugs targeting mammalian target of rapamycin (mTOR), a protein involved in nutrient sensing and metabolic regulation, are much more successful at limiting cell growth and proliferation in cultured cells than they are at slowing tumor growth in mouse cancer models and in patients (5). These observations argue that the tumor microenvironment affects cancer cell metabolism and can alter drug sensitivity.

Standard cell culture models of cancer do not mimic the tumor microenvironment. One major difference between classical cell culture conditions, where most drugs are initially tested, and tumors is the level of available nutrients. Indeed, most culture media formulations were not intended to mimic tumor physiology but were instead derived from experiments to identify the minimal nutrients required to grow mammalian cells in culture dishes (6). Levels of oxygen, which affect cancer cell metabolism and therapy response, have long been appreciated to be nonphysiologically elevated in standard culture conditions (7). Concentrations of other nutrients are different in tumors in vivo than in standard culture media, which alters cell metabolism and affects therapy response. For example, glioblastoma cells cultured in media that contains nutrients at physiological levels found in blood rely, to a lesser extent, on glutamine consumption for proliferation than the same cells in standard culture media (8). Importantly, glioblastoma tumors in mouse models in vivo produce rather than catabolize glutamine, and this difference has been attributed to artificial nutrient levels in standard culture media creating a nonphysiological state with respect to glutamine metabolism. Similarly, culturing lung cancer cells in medium containing nutrients at physiological levels also reduces the dependence on glutamine catabolism and reproduces the lack of glutaminase inhibitor sensitivity observed in vivo (9). Many cell culture formulations contain high levels of the amino acid cystine, which drives glutamine catabolism and sensitivity to glutaminase inhibitors. Cancer cells in tumors are exposed to lower cystine levels, which explains at least in part why glutaminase inhibitors are less effective at slowing the growth of tumors in mice derived from cells that are sensitive to these drugs in culture. Thus, nutrient levels are an important component of the tumor microenvironment that alters metabolism and drug responses.

Environmental nutrient levels can also alter the requirement for “recycling metabolism.” In culture, intracellular protein recycling to obtain amino acids (10) and recapture of acetate from histone modifications (11) is dispensable for cancer cell proliferation, but both become required for tumor growth in vivo, where many nutrients are more limiting. Catabolism of extracellular protein can also be used by cells as a source of amino acids (10). Most media formulations are protein deficient, but otherwise amino acid rich, which may limit protein catabolism. However, cells grown with limiting amino acids but physiological levels of the protein albumin, the most abundant protein in blood and tissues, rely on albumin to obtain amino acids for growth (5). Interestingly, this switch in nutrient acquisition affects drug response. mTOR signaling promotes growth under amino acid replete conditions but constrains protein catabolism. Therefore, cells relying on extracellular protein catabolism for growth are resistant to mTOR inhibition (5). Thus, differences in amino acid acquisition between tumor cells and cells in culture may contribute to the limited efficacy of mTOR inhibitors in the clinic.

The microenvironment influences phenotype

Cell-intrinsic factors, such as cell lineage and genetic mutations, define a metabolic network that the cell is capable of using. However, the way this network operates is constrained by available nutrients and stromal interactions in the microenvironment. Thus, identical cells in different metabolic microenvironments exhibit distinct metabolic programs and variation in phenotypes, such as drug response.

GRAPHIC: C. BICKEL/SCIENCE

Cancer cells in tumors have access to nutrients that are not always added to standard cell culture media. For instance, the presence of uric acid, a nucleotide breakdown product found in vivo but absent from cell culture media, renders cells resistant to the pyrimidine analog and chemotherapeutic drug 5-fluorouracil, which is a standard treatment for many cancers (12). Furthermore, the addition of pyruvate to cell culture media alters the cellular redox state, which limits the ability of the antidiabetic drug metformin (which may also benefit some patients with cancer) to slow cancer cell proliferation (13). The altered sensitivity to these widely used drugs illustrates that microenvironmental nutrient levels can affect metabolic pathway use and response to metabolism-targeted therapy.

The tumor microenvironment also contains numerous cell types that can interact metabolically with cancer cells. Noncancer cells within a tumor can share metabolites with cancer cells, compete with cancer cells for nutrients, and provide signals that alter cancer cell metabolic pathway utilization. For example, competition between cancer cells and infiltrating lymphocytes for limited nutrients, and secretion of metabolic byproducts by cancer cells, can create an immunosuppressive microenvironment that limits antitumor immune responses (14). Thus, understanding the tumor microenvironment may even lead to improved therapies that control cancer via noncell autonomous mechanisms such as immunotherapy.

Relying on in vivo models to identify cancer targets is impractical, but current scalable ex vivo models are inaccurate with respect to microenvironment. Microenvironmental factors clearly alter drug responses, and differences in nutrient levels between tumors and normal tissues could even drive targetable liabilities of cancer cells. Different nutrient levels across tissues might also influence where specific cancers can thrive as metastases. Therefore, identifying how nutrients vary in tissue and tumor microenvironments and efforts to model this in tractable culture systems will be crucial to identify patients likely to respond to both existing and new drugs that target cancer processes, such as metabolism. Tumor nutrient levels also fluctuate both spatially and temporally within an individual tumor and could be affected by additional factors such as diet. This metabolic heterogeneity could be an important component of tumor heterogeneity that limits therapeutic effectiveness. Thus, defining physiological levels of nutrients and how physiology constrains cell metabolic processes could lead to a better understanding of drug responses and uncover new therapeutic opportunities. By combining knowledge of the nutritional microenvironment with models that consider other features of the tumor microenvironment, such as organoid culture, ex vivo models could be generated that might have better predictive power for drug response in patients with cancer, as well as with other diseases (15). Ultimately, redefining culture conditions to incorporate knowledge of the tumor microenvironment could transform our understanding of cell physiology and eliminate a bottleneck in identifying new cancer therapeutics.

References and Notes

Acknowledgments: The authors thank B. Bevis for assistance with the figure and acknowledge support from the Massachusetts Institute of Technology (MIT) Center for Precision Cancer Medicine, the Lustgarten Foundation, the Ludwig Center at MIT, SU2C, Howard Hughes Medical Institute, and the National Cancer Institute (F32CA213810 to A.M. and R01CA168653 to M.G.V.H.). M.G.V.H. is a consultant and scientific advisory board member for Agios Pharmaceuticals and Aeglea Biotherapeutics.
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