Mitochondrial transfer from cancer-associated fibroblasts increases migration in aggressive breast cancer.

Cancer-associated fibroblasts (CAFs) have distinct roles within the tumor microenvironment, which can impact the mode and efficacy of tumor cell migration. CAFs are known to increase invasion of less-aggressive breast cancer cells through matrix remodeling and leader-follower dynamics. Here, we demonstrate that CAFs communicate with breast cancer cells through the formation of contact-dependent tunneling nanotubes (TNTs), which allow for the exchange of cargo between cell types. CAF mitochondria are an integral cargo component and are sufficient to increase the 3D migration of cancer cells. This cargo transfer results in an increase in mitochondrial ATP production in cancer cells, whereas it has a negligible impact on glycolytic ATP production. Manually increasing mitochondrial oxidative phosphorylation (OXPHOS) by providing extra substrates for OXPHOS fails to enhance cancer cell migration unless glycolysis is maintained at a constant level. Together, these data indicate that tumor-stromal cell crosstalk via TNTs and the associated metabolic symbiosis is a finely controlled mechanism by which tumor cells co-opt their microenvironment to promote cancer progression and may become a potential therapeutic target.

Ovarian Cancer Cell-Conditioning Medium Induces Cancer-Associated Fibroblast Phenoconversion through Glucose-Dependent Inhibition of Autophagy.

One aspect of ovarian tumorigenesis which is still poorly understood is the tumor-stroma interaction, which plays a major role in chemoresistance and tumor progression. Cancer-associated fibroblasts (CAFs), the most abundant stromal cell type in the tumor microenvironment, influence tumor growth, metabolism, metastasis, and response to therapy, making them attractive targets for anti-cancer treatment. Unraveling the mechanisms involved in CAFs activation and maintenance is therefore crucial for the improvement of therapy efficacy. Here, we report that CAFs phenoconversion relies on the glucose-dependent inhibition of autophagy. We show that ovarian cancer cell-conditioning medium induces a metabolic reprogramming towards the CAF-phenotype that requires the autophagy-dependent glycolytic shift. In fact, 2-deoxy-D-glucose (2DG) strongly hampers such phenoconversion and, most importantly, induces the phenoreversion of CAFs into quiescent fibroblasts. Moreover, pharmacological inhibition (by proline) or autophagy gene knockdown (by siBECN1 or siATG7) promotes, while autophagy induction (by either 2DG or rapamycin) counteracts, the metabolic rewiring induced by the ovarian cancer cell secretome. Notably, the nutraceutical resveratrol (RV), known to inhibit glucose metabolism and to induce autophagy, promotes the phenoreversion of CAFs into normal fibroblasts even in the presence of ovarian cancer cell-conditioning medium. Overall, our data support the view of testing autophagy inducers for targeting the tumor-promoting stroma as an adjuvant strategy to improve therapy success rates, especially for tumors with a highly desmoplastic stroma, like ovarian cancer.

Historical perspective of tumor glycolysis: A century with Otto Warburg.

Tumors have long been known to rewire their metabolism to endorse their proliferation, growth, survival, and invasiveness. One of the common characteristics of these alterations is the enhanced glucose uptake and its subsequent transformation into lactic acid by means of glycolysis, regardless the availability of oxygen or the mitochondria effectiveness. This phenomenon is called the "Warburg effect", which has turned into a century of age now, since its first disclosure by German physiologist Otto Heinrich Warburg. Since then, this peculiar metabolic switch in tumors has been addressed by extensive studies covering several areas of research. In this historical perspective, we aim at illustrating the evolution of these studies over time and their implication in various fields of science.

Species-Deconvolved Proteomics for In Situ Investigation of Tumor-Stroma Interactions after Treatment of Pancreatic Cancer Patient-Derived Xenografts with Combined Gemcitabine and Paclitaxel.

Tumor-stroma interactions are critical in pancreatic ductal adenocarcinoma (PDAC) progression and therapeutics. Patient-derived xenograft (PDX) models recapitulate tumor-stroma interactions, but the conventional antibody-based immunoassay is inadequate to discriminate tumor and stromal proteins. Here, we describe a species-deconvolved proteomics approach embedded in IonStar that can unambiguously quantify the tumor (human-derived) and stromal (mouse-derived) proteins in PDX samples, enabling unbiased investigation of tumor and stromal proteomes with excellent quantitative reproducibility. With this strategy, we studied tumor-stroma interactions in PDAC PDXs that responded differently to Gemcitabine combined with nab-Paclitaxel (GEM+PTX) treatment. By analyzing 48 PDX animals 24 h/192 h after treatment with/without GEM+PTX, we quantified 7262 species-specific proteins under stringent cutoff criteria, with high reproducibility. For the PDX sensitive to GEM+PTX, the drug-dysregulated proteins in tumor cells were involved in suppressed oxidative phosphorylation and the TCA cycle, and in the stroma, inhibition of glycolytic activity was predominant, suggesting a relieved reverse Warburg effect by the treatment. In GEM+PTX-resistant PDXs, protein changes suggested extracellular matrix deposition and activation of tumor cell proliferation. Key findings were validated by immunohistochemistry (IHC). Overall, this approach provides a species-deconvolved proteomic platform that could advance cancer therapeutic studies by enabling unbiased exploration of tumor-stroma interactions in the large number of PDX samples required for such investigations.

TGF-ß1 induced autophagy in cancer associated fibroblasts during hypoxia contributes EMT and glycolysis via MCT4 upregulation.

The Transforming growth factor-ß1 (TGF- ß1) in the tumor microenvironment (TME) is the major cytokine that acts as a mediator of tumor-stroma crosstalk, which in fact has a dual role in either promoting or suppressing tumor development. The cancer-associated fibroblasts (CAFs) are the major cell types in the TME, and the interaction with most of the epithelial cancers is the prime reason for cancer survival. However, the molecular mechanisms, associated with the TGF- ß1 induced tumor promotion through tumor-CAF crosstalk are not well understood. In the Reverse Warburg effect, CAFs feed the adjacent cancer cells by lactate produced during the aerobic glycolysis. We hypothesized that the monocarboxylate transporter, MCT4 which is implicated in lactate efflux from the CAFs, must be overexpressed in the CAFs. Contextually, to explore the role of TGF- ß1 in the hypoxia-induced autophagy in CAFs, we treated CoCl2 and external TGF- ß1 to the human dermal fibroblasts and L929 murine fibroblasts. We demonstrated that hypoxia accelerated the TGF- ß1 signaling and subsequent transformation of normal fibroblasts to CAFs. Moreover, we elucidated that synergistic induction of autophagy by hypoxia and TGF- ß1 upregulate the aerobic glycolysis and MCT4 expression in CAFs. Furthermore, we showed a positive correlation between glucose consumption and MCT4 expression in the CAFs. Autophagy was also found to be involved in the EMT in hypoxic CAFs. Collectively, these findings reveal the unappreciated role of autophagy in TME, which enhances the CAF transformation and that promotes tumor migration and metastasis via the reverse Warburg effect.

Microeconomics of Metabolism: The Warburg Effect as Giffen Behaviour.

Metabolic behaviours of proliferating cells are often explained as a consequence of rational optimization of cellular growth rate, whereas microeconomics formulates consumption behaviours as optimization problems. Here, we pushed beyond the analogy to precisely map metabolism onto the theory of consumer choice. We thereby revealed the correspondence between long-standing mysteries in both fields: the Warburg effect, a seemingly wasteful but ubiquitous strategy where cells favour aerobic glycolysis over more energetically efficient oxidative phosphorylation, and Giffen behaviour, the unexpected consumer behaviour where a good is demanded more as its price rises. We identified the minimal, universal requirements for the Warburg effect: a trade-off between oxidative phosphorylation and aerobic glycolysis and complementarity, i.e. impossibility of substitution for different metabolites. Thus, various hypotheses for the Warburg effect are integrated into an identical optimization problem with the same universal structure. Besides, the correspondence between the Warburg effect and Giffen behaviour implies that oxidative phosphorylation is counter-intuitively stimulated when its efficiency is decreased by metabolic perturbations such as drug administration or mitochondrial dysfunction; the concept of Giffen behaviour bridges the Warburg effect and the reverse Warburg effect. This highlights that the application of microeconomics to metabolism can offer new predictions and paradigms for both biology and economics.

Metabolic Relationship Between Cancer-Associated Fibroblasts and Cancer Cells.

Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME), play an important role in cancer initiation, progression, and metastasis. Recent findings have demonstrated that the TME not only provides physical support for cancer cells but also directs cell-to-cell interactions (in this case, the interaction between cancer cells and CAFs). As cancer progresses, the CAFs also coevolve, transitioning from an inactivated state to an activated state. The elucidation and understanding of the interaction between cancer cells and CAFs will pave the way for new cancer therapies [1-3].

Tumoral microvesicle-activated glycometabolic reprogramming in fibroblasts promotes the progression of oral squamous cell carcinoma.

Metabolic reprogramming is a hallmark of cancer. Stromal cells could function as providers of energy metabolites for tumor cells by undergoing the "reverse Warburg effect," but the mechanism has not been fully elucidated. The interaction between the tumoral microvesicles (TMVs) and stroma in the tumor microenvironment plays a critical role in facilitating cancer progression. In this study, we demonstrated a novel mechanism for the TMV-mediated glycometabolic reprogramming of stromal cells. After being incubated with TMVs, normal human gingival fibroblasts exhibited a phenotype switch to cancer-associated fibroblasts and underwent a degradation of caveolin 1 (CAV1) through the ERK1/2-activation pathway. CAV1 degradation further induced the metabolic switch to aerobic glycolysis in the fibroblasts. The microvesicle-activated fibroblasts absorbed more glucose and produced more lactate. The migration and invasion of oral squamous cell carcinoma (OSCC) were promoted after being cocultured with the activated fibroblasts. Fibroblast-cancer cell glycometabolic coupling ring mediated by monocarboxylate transporter (MCT) 4 and MCT1 was then proved in the tumor microenvironment. Results indicated a mechanism for tumor progression by the crosstalk between tumor cells and stromal cells through the reverse Warburg effect via TMVs, thereby identifying potential targets for OSCC prevention and treatment.-Jiang, E., Xu, Z., Wang, M., Yan, T., Huang, C., Zhou, X., Liu, Q., Wang, L., Chen, Y., Wang, H., Liu, K., Shao, Z., Shang, Z. Tumoral microvesicle-activated glycometabolic reprogramming in fibroblasts promotes the progression of oral squamous cell carcinoma.

Lactate and Lactate Transporters as Key Players in the Maintenance of the Warburg Effect.

Reprogramming of energy metabolism is a key hallmark of cancer. Most cancer cells display a glycolytic phenotype, with increased glucose consumption and glycolysis rates, and production of lactate as the end product, independently of oxygen concentrations. This phenomenon, known as "Warburg Effect", provides several survival advantages to cancer cells and modulates the metabolism and function of neighbour cells in the tumour microenvironment. However, due to the presence of metabolic heterogeneity within a tumour, cancer cells can also display an oxidative phenotype, and corruptible cells from the microenvironment become glycolytic, cooperating with oxidative cancer cells to boost tumour growth. This phenomenon is known as "Reverse Warburg Effect". In either way, lactate is a key mediator in the metabolic crosstalk between cancer cells and the microenvironment, and lactate transporters are expressed differentially by existing cell populations, to support this crosstalk.In this review, we will focus on lactate and on lactate transporters in distinct cells of the tumour microenvironment, aiming at a better understanding of their role in the acquisition and maintenance of the direct/reverse "Warburg effect" phenotype, which modulate cancer progression.

Pyruvate secreted from patient-derived cancer-associated fibroblasts supports survival of primary lymphoma cells.

Cancer-associated fibroblasts (CAF) are a key component in the tumor microenvironment and play functional roles in tumor metastasis and resistance to chemotherapies. We have previously reported that CAF isolated from lymphoma samples increase anaerobic glycolysis and decrease intracellular production of reactive oxygen species, promoting the survival of tumor cells. Herein, we analyzed the mechanisms underlying this support of tumor-cell survival by CAF. As direct contact between lymphoma cells and CAF was not indispensable to survival support, we identified that the humoral factor pyruvate was significantly secreted by CAF. Moreover, survival of lymphoma cells was promoted by the presence of pyruvate, and this promotion was canceled by inhibition of monocarboxylate transporters. Metabolome analysis of lymphoma cells in coculture with CAF demonstrated that intermediates in the citric acid cycle were significantly increased, indicating that tumor cells produced energy by aerobic metabolism. These findings indicate that energy production in lymphoma cells is regulated in coordination not only with anaerobic glycolysis, but also with aerobic metabolism termed the reverse-Warburg effect, involving the secretion of pyruvate from CAF resulting in increased use of the citric acid cycle in lymphoma cells.

Warburg effect in Gynecologic cancers.

Mammalian cells produce energy by oxidative phosphorylation under aerobic conditions. However, in the 1920s, Otto Warburg reported the so-called "Warburg effect" in which cancer cells produce ATP that is biased toward glycolysis rather than mitochondrial oxidative phosphorylation not only in anaerobic environment but also in aerobic environment. Glucose is converted into lactate without going into mitochondria after being metabolized in glycolysis. Compared with oxidative phosphorylation, the glycolysis has a faster ATP production rate but it is very inefficient, resulting in cancer cells consuming a large amount of glucose. Increased glucose metabolism has become a biomarker for cancer cells and has led to the development of positron emission tomography with fluorodeoxyglucose. Till date, the Warburg effect has been an inefficient system for cancer cells with regard to efficient energy production, but since the consumption of oxygen can be suppressed as the tumor grows in mass, it is thought that the Warburg effect is advantageous in this situation wherein the tumor can increase despite the lack of vessels. In addition, an increased lactate by the glycolysis causes acidosis in the microenvironment of tissues, which is thought to damage the surrounding normal tissues and favor the invasion and metastasis of cancer. Thus, Warburg effect is one of the key mechanisms for cancer development and will be the next promising target. In this review, we introduce key players that can be targeted in the Warburg effect and outline the prospects of treatment, targeting the Warburg effect in gynecological cancer.

Metabolic Relationship between Cancer-Associated Fibroblasts and Cancer Cells.

KEY POINTS: Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME), play an important role in cancer initiation, progression, and metastasis. Recent findings have demonstrated that the TME not only provides physical support for cancer cells, but also directs cell-to-cell interactions (in this case the interaction between cancer cells and CAFs). As cancer progresses, the CAFs also co evolve­transitioning from an inactivated state to an activated state. The elucidation and understanding of the interaction between cancer cells and CAFs will pave the way for new cancer therapies [1­3]. The TME is a heterogeneous environment consisting of fibroblasts, tumor-associated macrophages, adipocytes, an extracellular matrix, and mesenchymal stem cells [4]. The exact composition of each stroma varies depending on cancer and tissue type. To add to this variation, there is heterogeneity even within the CAF population itself. Different CAFs express different markers and influence stromal pro-tumorigenic capacity and cancer progression in diverse ways [5, 6].

Metabolic Interplay between Tumour Cells and Cancer-Associated Fibroblasts (CAFs) under Hypoxia versus Normoxia.

The growth of tumour cells is closely related to cancer-associated fibroblasts (CAFs) present within their microenvironment. CAFs, the most abundant cells in tumour stroma, secrete growth factors that play pivotal roles in tumour cell proliferation, metabolism, angiogenesis and metastasis. Tumour cells adapt to rapid environmental changes from normoxia to hypoxia through metabolic interplay with CAFs. In this mini review, we discuss the role of lactate dehydrogenases (LDHs) and monocarboxylate transporters (MCTs) on the metabolic interplay between tumour cells and CAFs under hypoxia compared to normoxia. The LDHs catalyse the interchange of lactate and pyruvate, whereas MCTs facilitate the influx and efflux of monocarboxylates, especially lactate and pyruvate. To sum up, tumour cells switch their metabolic state between glycolysis and oxidative phosphorylation through metabolic interplay with CAFs, which exhibit the Warburg effect under hypoxia and reverse Warburg effect under normoxia.

Organ-Specific Cancer Metabolism and Its Potential for Therapy.

Targeting cancer metabolism 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, the 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.

Energy sources identify metabolic phenotypes in pancreatic cancer.

Metabolic reprogramming is one of the emerging hallmarks of cancers. As a highly malignant tumor, pancreatic ductal adenocarcinoma (PDA) is not only a metabolic disease but also a heterogeneous disease. Heterogeneity induces PDA dependence on distinct nutritive substrates, thereby inducing different metabolic phenotypes. We stratified PDA into four phenotypes with distinct types of energy metabolism, including a Warburg phenotype, a reverse Warburg phenotype, a glutaminolysis phenotype, and a lipid-dependent phenotype. The four phenotypes possess distinct metabolic features and reprogram their metabolic pathways to adapt to stress. The metabolic type present in PDA should prompt differential imaging and serologic metabolite detection for diagnosis and prognosis. The targeting of an individual metabolic phenotype with corresponding metabolic inhibitors is considered a promising therapeutic approach and, in combination with chemotherapy, is expected to be a novel strategy for PDA treatment.

A reverse Warburg metabolism in oral squamous cell carcinoma is not dependent upon myofibroblasts.

BACKGROUND: The reverse Warburg effect describes the phenomenon that epithelial cancer cells take advantage of the metabolic machinery from nearby cancer-associated fibroblast, inducing them to produce lactate and ketones to fuel the high metabolic demands of the epithelial tumour tissues. This is in breast cancer observed as a lack of stromal caveolin-1 (CAV-1) and an increased expression of monocarboxylate transporter 4 (MCT-4) in the tumour stroma, with a concomitant increase in the expression of monocarboxylate transporter 1 (MCT-1) in the epithelial, tumour compartment. The lack of CAV-1 and increased expression of MCT-4 have been shown to have prognostic importance, primarily in patients with breast cancer. However, this phenomenon has only scarcely been described in oral squamous cell carcinoma (OSCC). Given the prognostic importance of myofibroblasts in OSCC, we also examined a potential relationship between the expression of MCT-4 and the presence of myofibroblasts. METHODS: Paraffin-embedded tissues from 30 patients with OSCC were immunostained with antibodies towards MCT-1, MCT-4, Cav-1, GLUT-1, α-SMA, TOMM20 and KI-67, and evaluated for their specific epithelial and stromal expression. RESULTS AND CONCLUSIONS: In patients with OSCC, we find an increased expression of MCT-1 and MCT-4 in both the epithelial and stromal compartment, with almost no overlap in their spatial expression. We found a large spatial overlap between α-SMA and MCT-1 in the stroma compartment, but no relationship between MCT-4 and myofibroblasts. Interestingly, we did not observe any relationship between the absence of CAV-1 and the presence of MCT-4 as has been shown in breast carcinomas.

Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis.

BACKGROUND: Alcohol consumption promotes hepatocellular carcinoma (HCC). The responsible mechanisms are not well understood. Hepatocarcinogenesis increases with age and is enhanced by factors that impose a demand for liver regeneration. Because alcohol is hepatotoxic, habitual alcohol ingestion evokes a recurrent demand for hepatic regeneration. The alcohol-preferring (P) rat model mimics the level of alcohol consumption by humans who habitually abuse alcohol. Previously, we showed that habitual heavy alcohol ingestion amplified age-related hepatocarcinogenesis in P rats, with over 80% of alcohol-consuming P rats developing HCCs after 18 months of alcohol exposure, compared with only 5% of water-drinking controls. METHODS: Herein, we used quantitative real-time PCR and quantitative immunocytochemistry to compare liver tissues from alcohol-consuming P rats and water-fed P rat controls after 6, 12, or 18 months of drinking. We aimed to identify potential mechanisms that might underlie the differences in liver cancer formation and hypothesized that chronic alcohol ingestion would activate Hedgehog (HH), a regenerative signaling pathway that is overactivated in HCC. RESULTS: Chronic alcohol ingestion amplified age-related degenerative changes in hepatocytes, but did not cause appreciable liver inflammation or fibrosis even after 18 months of heavy drinking. HH signaling was also enhanced by alcohol exposure, as evidenced by increased levels of mRNAs encoding HH ligands, HH-regulated transcription factors, and HH target genes. Immunocytochemistry confirmed increased alcohol-related accumulation of HH ligand-producing cells and HH-responsive target cells. HH-related regenerative responses were also induced in alcohol-exposed rats. Three of these processes (i.e., deregulated progenitor expansion, the reverse Warburg effect, and epithelial-to-mesenchymal transitions) are known to promote cancer growth in other tissues. CONCLUSIONS: Alcohol-related changes in Hedgehog signaling and resultant deregulation of liver cell replacement might promote hepatocarcinogenesis.

Shikonin reverses cancer-associated fibroblast-induced gemcitabine resistance in pancreatic cancer cells by suppressing monocarboxylate transporter 4-mediated reverse Warburg effect.

BACKGROUND: Gemcitabine is a first-line chemotherapeutic agent for pancreatic cancer (PC); however, most patients who receive adjuvant gemcitabine rapidly develop resistance and recurrence. Cancer-associated fibroblasts (CAFs) are a crucial component of the tumor stroma that contribute to gemcitabine-resistance. There is thus an urgent need to find a novel therapeutic strategy to improve the efficacy of gemcitabine in PC cells under CAF-stimulation. PURPOSE: To investigate if shikonin potentiates the therapeutic effects of gemcitabine in PC cells with CAF-induced drug resistance. METHODS: PC cell-stimulated fibroblasts or primary CAFs derived from PC tissue were co-cultured with PC cells to evaluate the ability of shikonin to improve the chemotherapeutic effects of gemcitabine in vitro and in vivo. Glucose uptake assay, ATP content analysis, lactate measurement, real-time PCR, immunofluorescence staining, western blot, and plasmid transfection were used to investigate the underlying mechanism. RESULTS: CAFs were innately resistant to gemcitabine, but shikonin suppressed the PC cell-induced transactivation and proliferation of CAFs, reversed CAF-induced resistance, and restored the therapeutic efficacy of gemcitabine in the co-culture system. In addition, CAFs underwent a reverse Warburg effect when co-cultured with PC cells, represented by enhanced aerobic glycolytic metabolism, while shikonin reduced aerobic glycolysis in CAFs by reducing their glucose uptake, ATP concentration, lactate production and secretion, and glycolytic protein expression. Regarding the mechanism underlying these sensitizing effects, shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects. Furthermore, shikonin promoted the effects of gemcitabine in reducing the growth of tumors derived from PC cells and CAF co-inoculation in BALB/C mice, with no significant systemic toxicity. CONCLUSION: These results indicate that shikonin reduced MCT4 expression and activation, resulting in inhibition of aerobic glycolysis in CAFs and overcoming CAF-induced gemcitabine resistance in PC. Shikonin is a promising chemosensitizing phytochemical agent when used in combination with gemcitabine for PC treatment. The results suggest that disrupting the metabolic coupling between cancer cells and stromal cells might provide an attractive strategy for improving gemcitabine efficacy.

The Warburg effect: a score for many instruments in the concert of cancer and cancer niche cells.

Although Warburg's discovery of intensive glucose uptake by tumors, followed by lactate fermentation in oxygen presence of oxygen was made a century ago, it is still an area of intense research and development of new hypotheses that, layer by layer, unravel the complexities of neoplastic transformation. This seemingly simple metabolic reprogramming of cancer cells reveals an intriguing, multi-faceted nature that may link various phenomena including cell signaling, cell proliferation, ROS generation, energy supply, macromolecules synthesis/biosynthetic precursor supply, immunosuppression, or cooperation of cancerous cells with cancer-associated fibroblasts (CAFs), known as reversed Warburg effect. According to the current perception of the causes and consequences of the Warburg effect, PI3K/Akt/mTOR are the main signaling pathways that, in concert with the transcription factors HIF-1, p53, and c-Myc, modulate the activity/expression of key regulatory enzymes, including PKM2, and PDK1 to tune in the most optimal metabolic setting for the cancer cell. This in turn secures adequate levels of biosynthetic precursors, NADPH, NAD+, and rapid ATP production to meet the increased demands of intensively proliferating tumor cells. The end-product of "aerobic glycolysis", lactate, an oncometabolite, may provide fuel to neighboring cancer cells, and facilitate metastasis and immunosuppression together enabling cancer progression. The importance and possible applicability of the presented issue are best illustrated by numerous trials with various agents targeting the Warburg effect, constituting a promising strategy in future anti-cancer regimens. In this review, we present the key aspects of this multifactorial phenomenon, depicting the mechanisms and benefits behind the Warburg effect, and also pointing to selected aspects in the field of anticancer therapy.

Role of Glucose Metabolic Reprogramming in Breast Cancer Progression and Drug Resistance.

The involvement of glucose metabolic reprogramming in breast cancer progression, metastasis, and therapy resistance has been increasingly appreciated. Studies in recent years have revealed molecular mechanisms by which glucose metabolic reprogramming regulates breast cancer. To date, despite a few metabolism-based drugs being tested in or en route to clinical trials, no drugs targeting glucose metabolism pathways have yet been approved to treat breast cancer. Here, we review the roles and mechanisms of action of glucose metabolic reprogramming in breast cancer progression and drug resistance. In addition, we summarize the currently available metabolic inhibitors targeting glucose metabolism and discuss the challenges and opportunities in targeting this pathway for breast cancer treatment.