Metabolic strategies of melanoma cells: Mechanisms,interactions with the tumor microenvironment,and therapeutic implications

Melanomas are metabolically heterogeneous, and they are able to adapt in order to utilize a variety of fuels that facilitate tumor progression and metastasis. The significance of metabolism in melanoma is supported by growing evidence of impact on the efficacy of contemporary therapies for this disease. There are also data to support that the metabolic phenotypes of melanoma cells depend upon contributions from both intrinsic oncogenic pathways and extrinsic factors in the tumor microenvironment. This review summarizes current understanding of the metabolic processes that promote cutaneous melanoma tumorigenesis and progression, the regulation of cancer cell metabolism by the tumor microenvironment, and the impact of metabolic pathways on targeted and immune therapies.     

Metabolomic Changes Accompanying Transformation and Acquisition of Metastatic Potential in a Syngeneic Mouse Mammary Tumor Model

Breast cancer is the most common cancer type for women in the western world. Despite decades of research, the molecular processes associated with breast cancer progression are still inadequately defined. Here, we focus on the systematic alteration of metabolism by using the state of the art metabolomic profiling techniques to investigate the changes of 157 metabolites during the progression of normal mouse mammary epithelial cells to an isogenic series of mammary tumor cell lines with increasing metastatic potentials. Our results suggest a two-step metabolic progression hypothesis during the acquisition of tumorigenic and metastatic abilities. Metabolite changes accompanying tumor progression are identified in the intracellular and secreted forms in several pathways, including glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway, fatty acid and nucleotide biosynthesis, and the GSH-dependent antioxidative pathway. These results suggest possible biomarkers of breast cancer progression as well as opportunities of interrupting tumor progression through the targeting of metabolic pathways.     

乳酸代谢——肿瘤治疗新靶点

恶性肿瘤严重危害人类健康,其治疗目前主要有手术、放疗和化疗三种方式,但疗效尚无法达到令人满意的程度,因此寻找肿瘤治疗新靶点、实现肿瘤的靶向治疗非常迫切. Warburg效应普遍存在于多种肿瘤中,其重要特征是在氧气充足的条件下,癌细胞的能量代谢仍以糖酵解为主. Warburg效应是糖酵解的典型过程,葡萄糖被大量吸收并通过糖酵解转化为乳酸.糖酵解产物乳酸可以激活癌细胞中许多重要的信号通路,促进癌细胞的存活、侵袭、免疫逃逸、转移和血管生成.因此,靶向乳酸代谢过程及其关键酶可能为肿瘤治疗提供新的靶点.本文对肿瘤细胞代谢方式的改变,乳酸对肿瘤细胞免疫逃逸、肿瘤转移、肿瘤血管生成的影响,以及以乳酸为靶点的肿瘤治疗等方面进行综述.     

Antitumor effects of curcumin: A lipid perspective

Lipid metabolism plays an important role in cancer development due to the necessities of rapidly dividing cells to increase structural, energetic, and biosynthetic demands for cell proliferation. Basically, obesity, type 2 diabetes, and other related diseases, and cancer are associated with a common hyperactivated “lipogenic state.” Recent evidence suggests that metabolic reprogramming and overproduction of enzymes involved in the synthesis of fatty acids are the new hallmarks of cancer, which occur in an early phase of tumorigenesis. As the first evidence to confirm dysregulated lipid metabolism in cancer cells, the overexpression of fatty acid synthase (FAS) was observed in breast cancer patients and demonstrated the role of FAS in cancer. Other enzymes of fatty acid synthesis have recently been found to be dysregulated in cancer, including ATP-dependent citrate lyase and acetyl-CoA carboxylase, which further underscores the connection of these metabolic pathways with cancer cell survival and proliferation. The degree of overexpression of lipogenic enzymes and elevated lipid utilization in tumors is closely associated with cancer progression. The question that arises is whether the progression of cancer can be suppressed, or at least decelerated, by modulating gene expression related to fatty acid metabolism. Curcumin, due to its effects on the regulation of lipogenic enzymes, might be able to suppress, or even cause regression of tumor growth. This review discusses recent evidence concerning the important role of lipogenic enzymes in the metabolism of cancer cells and whether the inhibitory effects of curcumin on lipogenic enzymes is therapeutically efficacious.     

13C metabolic flux analysis clarifies distinct metabolic phenotypes of cancer cell spheroid mimicking tumor hypoxia

Cancer cells adapt their intracellular energy metabolism to the oxygen-deprived tumor microenvironment (TME) to ensure tumor progression. This adaptive mechanism has focused attention on the metabolic phenotypes of tumor cells under hypoxic TME for developing novel cancer therapies. Although widely used monolayer (2D) culture does not fully reflect in vivo hypoxic TME, spheroid (3D) culture can produce a milieu similar to the TME in vivo. However, how different metabolic phenotypes are expressed in 3D cultures mimicking tumor hypoxia compared with 2D cultures under hypoxia remains unclear. To address this issue, we investigated the metabolic phenotypes of 2D- and 3D-cultured cancer cells by ¹³C-metabolic flux analysis (¹³C-MFA). Principal component analysis of ¹³C mass isotopomer distributions clearly demonstrated distinct metabolic phenotypes of 3D-cultured cells. ¹³C-MFA clarified that 3D culture significantly upregulated pyruvate carboxylase flux in line with the pyruvate carboxylase protein expression level. On the other hand, 3D culture downregulated glutaminolytic flux. Consistent with our findings, 3D-cultured cells are more resistant to a glutaminase inhibitor than 2D-cultured cells. This study suggests the importance of considering the metabolic characteristics of the particular in vitro model used for research on cancer metabolism.     

The metabolic environment of cancer

The tumor cell has a very distinctive metabolism. It acts as a metabolic trap for host nutrients thus taking vital compounds for the metabolism of the host. Depending on the particular tumor growing pattern, cancer cells use preferentially glucose or amino acids for their energetic or biosynthetic needs. Lipids, fatty acids in particular, can also be taken up by the tumor cell. In addition, it can also release some compounds into the host circulation which are not normally produced by the original cell before neoplastic transformation. Some of these compounds affect the metabolism of the host in an unfavorable way since they can oppose the host's metabolic responses, which sustain homeostasis. The final product is that the metabolic machinery of these cells allows them to grow continuously in an uncontrolled manner. The consequences of tumor invasion on the host's metabolism are varied. They have, however, one thing in common: the reduction of the metabolic efficiency of the host. Muscular protein depletion, increased gluconeogenesis, uncoupling of oxidative phosphorylation constitute the main metabolic responses of the host as a result of tumor invasion. The net result of all these metabolic changes is profound energy imbalance which normally ends with cachexia and, eventually, death.     

Advance in metabolism and target therapy in breast cancer stem cells

Breast cancer, like many other cancers, is believed to be driven by a population of cells that display stem cell properties. Recent studies suggest that cancer stem cells (CSCs) are essential for tumor progression, and tumor relapse is thought to be caused by the presence of these cells. CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies. Additionally, the metabolic properties of cancer cells differ markedly from those of normal cells. The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells. Metabolic targeting of breast CSCs (BCSCs) may be a very effective strategy for anti-cancer treatment of breast cancer cells. Thus, in this review, we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.     

Effect of metabolism on the immune microenvironment of breast cancer

Breast cancer (BC) is a highly prevalent primary malignancy worldwide with poor prognosis. Despite the development of aggressive interventions, mortality due to BC remains high. BC cells reprogram nutrient metabolism to adapt to the energy acquisition and progression of the tumor.The metabolic changes in cancer cells are closely related to the abnormal function and effect of immune cells and immune factors, including chemokines, cytokines, and other related effector molecules in the tumor microenvironment (TME), leading to tumor immune escape, whereby the complex crosstalk between immune cells and cancer cells has been considered the key mechanism regulating cancer progression. In this review, we summarized the latest findings on metabolism-related processes in the immune microenvironment during BC progression. Our findings showing the impact of metabolism on the immune microenvironment may suggest new strategies for regulating the immune microenvironment and attenuating BC through metabolic interventions.     

Mitochondrial metabolism in cancer metastasis

We have recently proposed a new two-compartment model for understanding the Warburg effect in tumor metabolism. In this model, glycolytic stromal cells produce mitochondrial fuels (L-lactate and ketone bodies) that are then transferred to oxidative epithelial cancer cells, driving OXPHOS and mitochondrial metabolism. Thus, stromal catabolism fuels anabolic tumor growth via energy transfer. We have termed this new cancer paradigm the “reverse Warburg effect,” because stromal cells undergo aerobic glycolysis, rather than tumor cells. To assess whether this mechanism also applies during cancer cell metastasis, we analyzed the bioenergetic status of breast cancer lymph node metastases, by employing a series of metabolic protein markers. For this purpose, we used MCT4 to identify glycolytic cells. Similarly, we used TO MM20 and COX staining as markers of mitochondrial mass and OXPHOS activity, respectively. Consistent with the “reverse Warburg effect,” our results indicate that metastatic breast cancer cells amplify oxidative mitochondrial metabolism (OXPHOS) and that adjacent stromal cells are glycolytic and lack detectable mitochondria. Glycolytic stromal cells included cancer-associated fibroblasts, adipocytes and inflammatory cells. Double labeling experiments with glycolytic (MCT4) and oxidative (TO MM20 or COX) markers directly shows that at least two different metabolic compartments co-exist, side-by-side, within primary tumors and their metastases. Since cancer-associated immune cells appeared glycolytic, this observation may also explain how inflammation literally “fuels” tumor progression and metastatic dissemination, by “feeding” mitochondrial metabolism in cancer cells. Finally, MCT4(+) and TO MM20(-) “glycolytic” cancer cells were rarely observed, indicating that the conventional “Warburg effect” does not frequently occur in cancer-positive lymph node metastases.     

胃癌的肿瘤微环境研究进展

肿瘤微环境是决定肿瘤细胞行为的主要影响因素,有别于正常细胞与其周围组织所形成的微环境,组织缺氧和酸中毒、间质高压形成、大量生长因子和蛋白水解酶的产生及免疫炎性反应等构成了肿瘤组织代谢环境的生物学特征,这种特性在肿瘤的发生、进展、转移中扮演重要的角色。胃癌早期症状不典型、转移迅速、死亡率高,是消化系统最常见的恶性肿瘤,目前,关于肿瘤微环境的研究尚处于起步阶段,对胃癌肿瘤微环境的研究有助于我们进一步认识胃癌发生发展的机制,并为临床诊断、治疗胃癌提供依据。因此,本文就近年来在胃癌肿瘤微环境方面的研究进展作一综述。     

Integrin alpha9 (ITGA9) expression and epigenetic silencing in human breast tumors

Cancer metastasis is the major cause of cancer-associated death. Accordingly, identification of the regulatory mechanisms that control whether or not tumor cells become “directed walkers” is a crucial issue of cancer research. The deregulation of cell migration during cancer progression determines the capacity of tumor cells to escape from the primary tumors and invade adjacent tissues to finally form metastases. The ability to switch from a predominantly oxidative metabolism to glycolysis and the production of lactate even when oxygen is plentiful is a key characteristic of cancer cells. This metabolic switch, known as the Warburg effect, was first described in 1920s, and affected not only tumor cell growth but also tumor cell migration. In this review, we will focus on the recent studies on how cancer cell metabolism affects tumor cell migration and invasion. Understanding the new aspects on molecular mechanisms and signaling pathways controlling tumor cell migration is critical for development of therapeutic strategies for cancer patients.     

Thematic Review Series: Calorie Restriction and Ketogenic Diets: The ketogenic diet for the treatment of malignant glioma

Advances in our understanding of glioma biology has led to an increase in targeted therapies in preclinical and clinical trials; however, cellular heterogeneity often precludes the targeted molecules from being found on all glioma cells, thus reducing the efficacy of these treatments. In contrast, one trait shared by virtually all tumor cells is altered (dysregulated) metabolism. Tumor cells have an increased reliance on glucose, suggesting that treatments affecting cellular metabolism may be an effective method to improve current therapies. Indeed, metabolism has been a focus of cancer research in the last few years, as many pathways long associated with tumor growth have been found to intersect metabolic pathways in the cell. The ketogenic diet (high fat, low carbohydrate and protein), caloric restriction, and fasting all cause a metabolic change, specifically, a reduction in blood glucose and an increase in blood ketones. We, and others, have demonstrated that these metabolic changes improve survival in animal models of malignant gliomas and can potentiate the anti-tumor effect of chemotherapies and radiation treatment. In this review we discuss the use of metabolic alteration for the treatment of malignant brain tumors.     

Targeting amino acid metabolism in cancer growth and anti-tumor immune response

Recent advances in amino acid metabolism have revealed that targeting amino acid metabolic enzymes in cancer therapy is a promising strategy for the development of novel therapeutic agents. There are currently several drugs in clinical trials that specifically target amino acid metabolic pathways in tumor cells. In the context of the tumor microenvironment,however,tumor cells form metabolic relationships with immune cells,and they oftencompete for common nutrients. Many tumors evolved to escape immune surveillance by taking advantage of their metabolic flexibility and redirecting nutrients for their own advantage. This review outlines the most recent advances in targeting amino acid metabolic pathways in cancer therapy while giving consideration to the impact these pathways may have on the anti-tumor immune response.     

Tumor bioenergetics: An emerging avenue for cancer metabolism targeted therapy

Cell proliferation is a delicately regulated process that couples growth signals and metabolic demands to produce daughter cells. Interestingly, the proliferation of tumor cells immensely depends on glycolysis, the Warburg effect, to ensure a sufficient amount of metabolic flux and bioenergetics for macromolecule synthesis and cell division. This unique metabolic derangement ould provide an opportunity for developing cancer therapeutic strategy, particularly when other diverse anti-cancer treatments have been proved ineffective in achieving durable response, largely due to the emergence of resistance. Recent advances in deeper understanding of cancer metabolism usher in new horizons of the next generation strategy for cancer therapy. Here, we discuss the focused review of cancer energy metabolism, and the therapeutic exploitation of glycolysis and OXPHOS as a novel anti-cancer strategy, with particular emphasis on the promise of this approach, among other cancer metabolism targeted therapies that reveal unexpected complexity and context-dependent metabolic adaptability, complicating the development of effective strategies. [BMB Reports 2014; 47(3): 158-166]     

氨基酸转运体在肿瘤代谢中的研究进展

代谢重编程是肿瘤的重要特征,是指肿瘤细胞为满足其快速增殖的生物合成与能量需求,对其糖代谢、脂代谢以及氨基酸代谢等代谢路径进行的重编程,以维持增长速度以及补偿能量代谢所造成的氧化还原压力。虽然不同的癌症代谢变化不同,但有些特征是所有癌症共有的,氨基酸代谢重编程是其中一个重要的特征。氨基酸进出细胞需要氨基酸转运体的协助,因而在肿瘤细胞中多种特定的氨基酸转运体均过表达。靶向氨基酸转运体通过影响肿瘤细胞的氨基酸代谢从而达到抗肿瘤的目的,是目前抗肿瘤药物的研究热点之一。主要介绍了几种在肿瘤代谢中发挥重要作用的氨基酸转运体以及靶向氨基酸转运体抗肿瘤治疗的研究进展及相关作用机制,旨在了解氨基酸转运体在抗肿瘤研究中的作用,以期促进靶向氨基酸转运体抗肿瘤药物的发展。     

肿瘤中甲硫氨酸代谢及其相关基因的表达调控

甲硫氨酸(methionine)作为人体必需氨基酸,生理功能多样,在肿瘤代谢重编程过程中具有重要意义。研究发现,多种肿瘤细胞对外源性甲硫氨酸存在依赖性,该效应被称为Hoffman效应。在人体内,甲硫氨酸经甲硫氨酸循环代谢,参与一碳单位代谢、叶酸循环,以及多胺、谷胱甘肽、半胱氨酸和核苷酸等多种物质的合成。肿瘤中常出现甲硫氨酸代谢的改变,并伴随甲硫氨酸代谢相关酶基因表达的异常,其中以甲硫氨酸腺苷转移酶(methionine adenosyltransferase, MAT)相关基因表达改变及甲硫腺苷磷酸化酶(methylthioadenosine phosphorylase,MTAP)基因的缺失最为常见,二者可分别引起甲硫氨酸循环及甲硫氨酸补救合成途径的异常,进而导致甲基供体S-腺苷甲硫氨酸(S-adenosylmethionine, SAM)的生成减少和甲硫腺苷(methylthioadenosine, MTA)的堆积,其与肿瘤的发生、发展和转移等活动密切相关。由甲硫氨酸的代谢改变和代谢酶的基因表达异常,分别衍生出2种不同的治疗策略,即甲硫氨酸限制疗法和靶向治疗。本文将从甲硫氨酸代谢出发,阐述肿瘤中甲硫氨酸依懒性、肿瘤细胞MAT和MTAP相关基因的表达调控,并概述甲硫氨酸相关肿瘤治疗方案的新进展与新问题,为肿瘤治疗方案的进一步探索提供新思路。     

Lipid metabolism reprogramming in colorectal cancer

The hallmark feature of metabolic reprogramming is now considered to be widespread in many malignancies, including colorectal cancer (CRC). Of the gastrointestinal tumors, CRC is one of the most common with a high metastasis rate and long insidious period. The incidence and mortality of CRC has increased in recent years. Metabolic reprogramming also has a significant role in the development and progression of CRC, especially lipid metabolic reprogramming. Many studies have reported that lipid metabolism reprogramming is similar to the Warburg effect with typical features affecting tumor biology including proliferation, migration, local invasion, apoptosis, and other biological behaviors of cancer cells. Therefore, studying the role of lipid metabolism in the occurrence and development of CRC will increase our understanding of its pathogenesis, invasion, metastasis, and other processes and provide new directions for the treatment of CRC. In this paper, we mainly describe the molecular mechanism of lipid metabolism reprogramming and its important role in the occurrence and development of CRC. In addition, to provide reference for subsequent research and clinical diagnosis and treatment we also review the treatments of CRC that target lipid metabolism.     

Tumor mechanics and metabolic dysfunction

Desmosplasia is a characteristic of most solid tumors and leads to fibrosis through abnormal extracellular matrix (ECM) deposition, remodeling, and posttranslational modifications. The resulting stiff tumor stroma not only compromises vascular integrity to induce hypoxia and impede drug delivery, but also promotes aggressiveness by potentiating the activity of key growth, invasion, and survival pathways. Intriguingly, many of the protumorigenic signaling pathways that are mechanically activated by ECM stiffness also promote glucose uptake and aerobic glycolysis, and an altered metabolism is a recognized hallmark of cancer. Indeed, emerging evidence suggests that metabolic alterations and an abnormal ECM may cooperatively drive cancer cell aggression and treatment resistance. Accordingly, improved methods to monitor tissue mechanics and metabolism promise to improve diagnostics and treatments to ameliorate ECM stiffening and elevated mechanosignaling may improve patient outcome. Here we discuss the interplay between ECM mechanics and metabolism in tumor biology and suggest that monitoring these processes and targeting their regulatory pathways may improve diagnostics, therapy, and the prevention of malignant transformation.     

Determinants of nutrient limitation in cancer

Proliferation requires that cells accumulate sufficient biomass to grow and divide. Cancer cells within tumors must acquire a variety of nutrients, and tumor growth slows or stops if necessary metabolites are not obtained in sufficient quantities. Importantly, the metabolic demands of cancer cells can be different from those of untransformed cells, and nutrient accessibility in tumors is different than in many normal tissues. Thus, cancer cell survival and proliferation may be limited by different metabolic factors than those that are necessary to maintain noncancerous cells. Understanding the variables that dictate which nutrients are critical to sustain tumor growth may identify vulnerabilities that could be used to treat cancer. This review examines the various cell-autonomous, local, and systemic factors that determine which nutrients are limiting for tumor growth.