Abstract Lipid metabolic reprogramming is an emerging hallmark of cancer. In order to sustain uncontrolled proliferation and survive in unfavorable environments that lack oxygen and nutrients, tumor cells undergo metabolic transformations to exploit various ways of acquiring lipid and increasing lipid oxidation. In addition, stromal cells and immune cells in the tumor microenvironment also undergo lipid metabolic reprogramming, which further affects tumor functional phenotypes and immune responses. Given that lipid metabolism plays a critical role in supporting cancer progression and remodeling the tumor microenvironment, targeting the lipid metabolism pathway could provide a novel approach to cancer treatment. This review seeks to: (1) clarify the overall landscape and mechanisms of lipid metabolic reprogramming in cancer, (2) summarize the lipid metabolic landscapes within stromal cells and immune cells in the tumor microenvironment, and clarify their roles in tumor progression, and (3) summarize potential therapeutic targets for lipid metabolism, and highlight the potential for combining such approaches with other anti-tumor therapies to provide new therapeutic opportunities for cancer patients. 

Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics

Tumor metabolism is emerging as a potential target for cancer therapies. This new approach holds particular promise for the treatment of glioblastoma, a highly lethal brain tumor that is resistant to conventional treatments, for which improving therapeutic strategies is a major challenge. The presence of glioma stem cells is a critical factor in therapy resistance, thus making it essential to eliminate these cells for the long-term survival of cancer patients. Recent advancements in our understanding of cancer metabolism have shown that glioblastoma metabolism is highly heterogeneous, and that cancer stem cells exhibit specific metabolic traits that support their unique functionality. The objective of this review is to examine the metabolic changes in glioblastoma and investigate the role of specific metabolic processes in tumorigenesis, as well as associated therapeutic approaches, with a particular focus on glioma stem cell populations. 

/pdf/glioblastoma-metabolism-insights-and-therapeutic-strategies-2nzh5aw5.pdf

Glioblastoma Metabolism: Insights and Therapeutic Strategies

Mitochondria play a key role in cancer and their involvement is not limited to the production of ATP only. Mitochondria also produce reactive oxygen species and building blocks to sustain rapid cell proliferation; thus, the deregulation of mitochondrial function is associated with cancer disease development and progression. In cancer cells, a metabolic reprogramming takes place through a different modulation of the mitochondrial metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, the Krebs cycle, glutamine and heme metabolism. Alterations of mitochondrial homeostasis, in particular, of mitochondrial biogenesis, mitophagy, dynamics, redox balance, and protein homeostasis, were also observed in cancer cells. The use of drugs acting on mitochondrial destabilization may represent a promising therapeutic approach in tumors in which mitochondrial respiration is the predominant energy source. In this review, we summarize the main mitochondrial features and metabolic pathways altered in cancer cells, moreover, we present the best known drugs that, by acting on mitochondrial homeostasis and metabolic pathways, may induce mitochondrial alterations and cancer cell death. In addition, new strategies that induce mitochondrial damage, such as photodynamic, photothermal and chemodynamic therapies, and the development of nanoformulations that specifically target drugs in mitochondria are also described. Thus, mitochondria-targeted drugs may open new frontiers to a tailored and personalized cancer therapy.

/pdf/mitochondria-deregulations-in-cancer-offer-several-potential-356yi0uo.pdf

Mitochondria Deregulations in Cancer Offer Several Potential Targets of Therapeutic Interventions

Recent discoveries in cancer metabolism have revealed promising metabolic targets to modulate cancer progression, drug response, and anti-cancer immunity. Combination therapy, consisting of metabolic inhibitors and chemotherapeutic or immunotherapeutic agents, offers new opportunities for improved cancer therapy. However, it also presents challenges due to the complexity of cancer metabolic pathways and the metabolic interactions between tumor cells and immune cells. Many studies have been published demonstrating potential synergy between novel inhibitors of metabolism and chemo/immunotherapy, yet our understanding of the underlying mechanisms remains limited. Here, we review the current strategies of altering the metabolic pathways of cancer to improve the anti-cancer effects of chemo/immunotherapy. We also note the need to differentiate the effect of metabolic inhibition on cancer cells and immune cells and highlight nanotechnology as an emerging solution. Improving our understanding of the complexity of the metabolic pathways in different cell populations and the anti-cancer effects of chemo/immunotherapy will aid in the discovery of novel strategies that effectively restrict cancer growth and augment the anti-cancer effects of chemo/immunotherapy. 

Targeting cancer metabolic pathways for improving chemotherapy and immunotherapy.

Lipids, as one of the three primary energy sources, provide energy for all cellular life activities. Lipids are also known to be involved in the formation of cell membranes and play an important role as signaling molecules in the intracellular and microenvironment. Tumor cells actively or passively remodel lipid metabolism, using the function of lipids in various important cellular life activities to evade therapeutic attack. Breast cancer has become the leading cause of cancer-related deaths in women, which is partly due to therapeutic resistance. It is necessary to fully elucidate the formation and mechanisms of chemoresistance to improve breast cancer patient survival rates. Altered lipid metabolism has been observed in breast cancer with therapeutic resistance, indicating that targeting lipid reprogramming is a promising anticancer strategy. 

The lipid metabolism remodeling: A hurdle in breast cancer therapy.

The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM.The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO.GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group.ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM. 

/pdf/etomoxir-a-carnitine-palmitoyltransferase-1-inhibitor-1absyzdp.pdf

Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres

BACKGROUND A high proportion of pediatric patients with brain tumors (BTs) are known to experience a decline in neurocognitive function after treatment. We prospectively examined neuropsychological functioning of patients with BTs of varying tumor types at different time points before, during, and after proton beam therapy. MATERIALS AND METHODS A total of 98 patients with posterior fossa tumors (PFTs; n = 33), germ cell tumors (GCTs; n = 52), and other supratentorial tumors (STTs; n = 13) underwent baseline neuropsychological assessments and 57 patients underwent follow-up assessments. RESULTS All groups displayed significantly lower performance intelligence quotient (PIQ) and processing speed (PS) scores than the normative means at baseline. The PFT group exhibited significantly lower scores for full-scale IQ, PIQ, PS, attention, and executive function. The GCT group displayed full-scale IQ scores within the normal range, but a significantly high proportion had memory deficits. In the STT group, all functions except for the PIQ and PS were intact. Longitudinal evaluations demonstrated stable global IQ scores over time in all groups. In the PFT group, verbal comprehension, attention, and PS improved over time. However, in the GCT group, verbal IQ scores declined significantly and psychological problems worsened over time, which were correlated with poorer neurocognitive function at 3-5 years after treatment. In the STT group, no significant changes were observed. CONCLUSION Because patients with BTs exhibit various types of neurocognitive deficit before radiotherapy, early cognitive treatment tailored to the tumor type maybe beneficial. Interventions for psychological problems and memory function may be necessary, especially for patients with GCT.

Neurocognitive and psychological functioning of pediatric brain tumor patients undergoing proton beam therapy for three different tumor types

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Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres

Neurocognitive and psychological functioning of pediatric brain tumor patients undergoing proton beam therapy for three different tumor types