Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications

Zhong et al. Journal of Hematology & Oncology (2022) 15:160 https://doi.org/10.1186/s13045-022-01358-5 Open Access REVIEW Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications Xinyang Zhong1,5†, Xuefeng He1,5†, Yaxian Wang1,5, Zijuan Hu2,3,4,5, Huixia Huang2,3,4,5, Senlin Zhao1,5, Ping Wei2,3,4,5* and Dawei Li1,5* Abstract Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. Countless CRC patients undergo disease progression. As a hallmark of cancer, Warburg effect promotes cancer metastasis and remodels the tumor microenvironment, including promoting angiogenesis, immune suppression, cancer-associated fibroblasts formation and drug resistance. Targeting Warburg metabolism would be a promising method for the treatment of CRC. In this review, we summarize information about the roles of Warburg effect in tumor microenvironment to elucidate the mechanisms governing Warburg effect in CRC and to identify novel targets for therapy. Keywords: Colorectal cancer, Warburg effect, Metastasis, Tumor microenvironment, Therapeutics Background Cancer cells utilize lots of nutrients to sustain infinite proliferation and growth. This requires reprogramming of energy metabolism which is considered one of the hallmarks of cancer [1]. Moreover, alteration in energy metabolism leads to nutrition deficiency and metabolic waste accumulation, influencing the biological behavior of nearby non-tumor cells [2]. During the glycolysis process, cells break down glucose to produce pyruvate and a small amount of ATP. In normal cells with sufficient oxygen levels, pyruvate could enter the tricarboxylic acid (TCA) cycle to generate abundant energy whereas tumor cells exhibit high glycolysis activity † Xinyang Zhong and Xuefeng He contributed equally to this work. *Correspondence: ; 1 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China 2 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China Full list of author information is available at the end of the article regardless of the oxygen levels and produce lactate through activation of lactate dehydrogenase (LDH) and inhibition of pyruvate metabolism in mitochondria [3]. Such phenomenon was first observed by Otto H. Warburg in the early twentieth century and called the Warburg effect or aerobic glycolysis [4]. Aerobic glycolysis could meet the energy and nutrition demands essential for severe living conditions of tumor cells for cancer progression [3]. The role of glycolytic metabolism in cancer cells and nearby tumor microenvironment is complex and diverse. For example, enhanced glycolysis in cancerous cells relies on LDH-mediated production of NAD+ from NADH, reducing NADH:NAD+ ratio and suppressing p53 function [5]. In murine TNBC models, inhibition of glycolysis reduces the expression of cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) as well as the amount of myeloid-derived suppressor cells (MDSCs), further upregulating T cell immunity and inhibiting tumor development [6]. Herein, we summarize the oncogenic © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhong et al. Journal of Hematology & Oncology (2022) 15:160 mechanisms of aerobic glycolysis, highlighting the latest developments and exploring the relation with some novel concepts. Although various treatments can be used to treat colorectal cancer (CRC), the major concern that leads to CRC-related death nowadays is the metastasis of CRC [7]. Approximately half of the CRC patients could occur simultaneous or asynchronous metastases in liver, which becomes the most frequent metastatic organ in CRC [8, 9]. Surgical resection is suitable only for a small proportion of patients and chemotherapeutic treatment eventually leads to cancer progression due to initial or acquired resistance, highlighting the importance to develop new effective treatment [10– 12]. The tumor microenvironment (TME) has rapidly gained attention in cancer research for the past several years. The tumor microenvironment includes the surrounding cellular environment around the tumor cells such as endothelial cells, immune cells, fibroblasts, mesenchymal stem cells (MSCs), and the extracellular matrix (ECM) [13]. A series of cytokines, chemokines, growth factors, exosomes, and other signaling molecules interact with each other and constitute a network within the TME to give tumor the ability to sustain and survive the increased stress, leading to cancer metastasis, immune suppression, abnormal angiogenesis, and drug resistance [13–15]. Abnormal glycolysis within TME can strongly impact the hallmarks of cancer and the function and composition of immune cells. For example, regulatory T (Treg) cells utilize lactic acid and promote the nuclear translocation of NFAT1, upregulating PD-1 expression in highly-glycolytic tumors [16]. Meanwhile, the impaired PD-1 expression in effector T cells leads to unsatisfactory results of immunotherapy [16]. Thus, it becomes important to explore the interplay between dysregulated metabolism and abnormal tumor immune microenvironment (TIME). In this passage, we summarized the influence of the Warburg effect on the metastatic ability of CRC and the role of Warburg effect in the microenvironment remodeling of colorectal cancer, mainly focusing our attention on glycolytic metabolism in immune cells. Further, we discuss the effect of glycolytic metabolism on CRC therapy to explore whether glycolysis-related enzymes, transporters, and transcription factors can be of therapeutic importance in cancer treatment. We summarize several relevant small-molecule inhibitors that have been used in preclinical and clinical trials to act as adjuvant therapy strategies, increasing the effectiveness of existing programs. (...truncated)