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What is Cancer Metabolism?

Cancer is arguably one of the largest threats to global public health. The physical, emotional, and financial burden on cancer patients and their families is unsustainable, affecting the healthcare system and the economy. According to the International Agency for Research on Cancer, in 2018, there were 18.1 million new cancer diagnoses and 9.5 million deaths from cancer worldwide (1). In the year 2040, these statistics are predicted to rise to 29.5 million new cancer diagnoses and 16.4 million cancer deaths (1). Therefore, understanding the pathogenesis of cancer, improving diagnostics, and developing tailored, less toxic treatments is critical to minimizing the global healthcare and economic burden.

Cancer is a disease characterized by the excessive growth and division of abnormal cells (2). Under specific conditions, one aberrant cancer cell can proliferate into billions of cells, forming a large tumor. In fact, the average number of cells in a tumor approximately 1 centimeter in diameter is 109 cells (3). This accelerated and uncontrolled cellular proliferation can be a result of genetic changes that hijack signaling pathways important for cell division, cellular metabolism, and homeostasis. As a result, cancer cells can meet metabolic and anabolic demands that perpetuate excessive cell proliferation and cancer growth (3). The mechanisms by which cancer cells harness energy to grow and metastasize is termed cancer metabolism. Specifically, cancer cells consume glucose, glutamine, and serine as the first, second, and third most consumed metabolites, respectively (3). These metabolites are repurposed from healthy cells to facilitate cancer metabolism to support cancer survival, growth, and metastasis (Figure 1). One example of a cancer- driven metabolic pathway is via the induction of COXII (Figure 1a). COXII is a membrane-bound enzyme that is responsible for the oxidation of arachidonic acid into the prostaglandin (PGG2), and the reduction of PGG2 to PGH2 (Figure 1 b, c). This reaction mediated by COXII results in increased inflammatory response, increased apoptotic resistance, increased cellular proliferation and angiogenesis, enabling invasion/metastasis and hypoxia in the tumor micro environment (Figure 1d). Moreover, the hypoxic state in the tumor microenvironment can induce resistance to chemotherapeutic drugs, further highlighting the importance of studying cancer metabolism to create targeted and effective treatments (Figure 1 e). Cancer metabolism will in turn upregulate IDO, and ARG1 to drive immune suppression via T cell and Natural Killer (NK) cell suppression (Figure 1 f). It will also upregulate iNOS, resulting in nitric oxide production and aberrant cellular signaling. These genetic alterations further affect cellular metabolism in the tumor microenvironment to stimulate inflammatory/growth factors and cytokines (Figure 1 i). These cytokines and factors will in turn continue to induce COXII and cancer metabolism is maintained (Figure 1 j). Therefore, disrupting any part of this pathway can be a possible treatment toward derailing cancer metabolism and killing cancer cells. The unique metabolic signature of cancer cells reveals abundant opportunities for researchers to target, slow, and kill cancer cell progression.
cancer cell metabolic pathway

Figure 1. One example of a cancer cell metabolic pathway that drives pathogenesis and metastasis of cancer. Targeting these pathways can result in opportunities to develop novel and effective treatments


What we have learned about cancer metabolism and cancer treatment so far:

Our comprehensive understanding of cancer biology and cancer treatment has been advancing for centuries. Autopsies first performed in the eighteenth century have shed light on cancer pathogenesis and provided the fundamentals of oncology. Today, genetic sequencing can reveal previously inaccessible information about cancer risk and prognosis if a person is diagnosed with cancer. Early methods to study cancer (e.g., microscopic examination and enzyme assays) lead to developing anti-folates as some of the first cancer treatments to target cancer metabolism (2). Furthermore, kinase inhibitors have efficacy as anti-cancer drugs, but these are only a tiny portion of potential biochemical entry points to exploit cancer metabolism to treat cancer. While the entirety of the cancer metabolome is not fully understood, many key molecular players and substrates have been uncovered, allowing for a limited yet fundamental understanding of cancer metabolism and cancer pathogenesis for advances in treatment options in the fight against cancer.

The primary focus of cancer metabolism research is on developing drugs that lead to metabolic reprogramming in cancer cells by altering or inhibiting the activity of crucial enzymes and transporters that are part of cancer metabolic pathways. For example, cancer cells satisfy a portion of their energy demand by the oxidation of glucose, glutamine, and serine coupled to the electron transport chain (ETC). Some examples of treatments targeting the cancer metabolic pathway currently under investigation are the electron transport chain (ETC) complex I inhibitor metformin, Monocarboxylate Transporter (MCT) inhibitors, and Glutaminase (GLS) inhibitors. MCTs are important for maintaining cancer metabolism by transporting lactate out of cells. Since cancer cells rely on that lactate to grow, inhibitors of MCTs are being studied as potential drug targets (3). Furthermore, cytokine signaling from ovarian cancer cells will stimulate adipocytes to release fatty acids for cancer cell metabolism, therefore these fatty acids have been a target under investigation for anti-cancer drugs as well (3). Current technologies have enabled a detailed understanding of cancer metabolism and cancer treatments, yet many questions still remain.

What questions remain and how can we investigate them?

The thousands of mechanisms involved in cancer metabolism are not fully elucidated. For example, what is the role of one-carbon metabolism in the tumor microenvironment to facilitate cancer progression? The one-carbon pool for synthesis of purines occurs in the mitochondria and is facilitated by the enzyme MTHFD2 (5,10-methenyl-THF dehydrogenase 2), which is highly expressed in cancer tissues (3). However, the efficacy of drugs targeting mitochondrial one-carbon metabolism in cancer cells is still opaque and remains under investigation. One way to understand this is to investigate mitochondrial dysfunction in cancer versus normal cells. Additionally, what are the mechanisms allowing hypoxic cancer cells to demonstrate resistance to chemotherapeutic drugs? This phenomenon is a major setback that must continue to be studied. Experimental methods that specifically uncouple hypoxia and oxidative stress in various contexts are necessary to begin to understand this. Since cancer metabolism is complex and context-dependent, a paradox exists where autophagy in tumor cells can be the result of effective chemotherapy killing cancer cells, while on the other hand autophagy is important for maintaining survival of some cancers in nutrient-poor conditions (3). Therefore, understanding autophagy and apoptosis in various cancer types individually is critical to delivering the best course of treatment.

Taken together, avenues for treatment are waiting to be discovered. Unlike radiation therapy that globally harms living cells in addition to cancer cells, chemotherapy and biologics can be used to specifically target areas of cancer metabolism that result in a very specific effect on cancer cells, while leaving healthy cells thriving. Investigating these complex metabolic pathways for potential therapeutic targets require highly sensitive and accurate experimental methods with specific molecular targets and outcomes.

Partner with Enzo to join the fight against cancer:

Enzo Life Sciences has been in the fight against cancer for decades by producing state of the art technology for research and diagnostics. Some examples of the way in which Enzo’s portfolio of cancer metabolism products can accelerate your research is with our extensively benchmarked and validated ELISAs, antibodies, and cellular assays. For example, the COX-2 (human), ELISA kit is a complete kit for the quantitative determination of human COXII in cell culture lysates, providing valuable information about the tumor microenvironment. Additionally, Enzo’s ROS-ID® Hypoxia/Oxidative stress detection kit is specifically formulated for the detection and simultaneous analysis of hypoxia and oxidative stress in cells using either microscopy or flow cytometry as a readout. To further investigate markers of cancer metabolism, IDO and iNOS are upregulated in many cancers and can be valuable for determining the mechanism driving the cancer pathogenesis is your samples (Figure 1 f).

In compliment with our antibodies, Researchers can also integrate potential anti-oxidants or anti-cancer compounds using Enzo’s compound libraries such as the SCREEN-WELL® Cancer Library, and measure their effect on cancer cells using Enzo’s Lactate Dehydrogenase (LDH) Cytotoxicity WST Assay to quantitate the cytotoxicity via lactate dehydrogenase activity. In addition, the CYTO-ID® Autophagy detection kit will provide critical insight into autophagy of cancer cells in the context of various compounds targeting the cancer metabolism pathway. For more Enzo solutions to studying cancer metabolism, visit our cancer, immuno-oncology and oxidative stress webpages. The scientists at Enzo Life Sciences are eager to help you succeed. Contact our Technical Support Team for further assistance.

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References:

  1. Bray, Freddie, et al. “Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.” CA: A Cancer Journal for Clinicians, vol. 68, no. 6, 2018, pp. 394–424., doi:10.3322/caac.21492.
  2. Cancer statistics. (2020, September 25). Retrieved April 02, 2021.
  3. Vazquez, A., Kamphorst, J. J., Markert, E. K., Schug, Z. T., Tardito, S., Gottlieb, E. (2016). Cancer metabolism at a glance. Journal of Cell Science, 129(18), 3367-3373. doi:10.1242/jcs.181016

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