Hypoxia induced lactate acidosis modulates tumor microenvironment and lipid reprogramming to sustain the cancer cell survival

Singh, Lakhveer; Nair, Lakshmi S.; Kumar, Dinesh; Arora, Mandeep Kumar; Bajaj, Sakshi; Gadewar, Manoj; Mishra, Shashank Shekher; Rath, Santosh Kumar; Dubey, Amit Kumar; Kaithwas, Gaurav; Choudhary, Manjusha; Singh, Manjari

doi:10.3389/fonc.2023.1034205

Cited by 15 publications

(9 citation statements)

References 113 publications

(132 reference statements)

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“…Through this metabolic pathway, elevated amounts of lactate, protons (H + ), and carbon dioxide (CO 2 ) are secreted into TME. This leads to acidosis [ 213 ]. Acidosis regulates the metabolism of innate and adaptive immune cells by: (i) hindering the function of CD8 + T, natural killer (NK), natural killer T (NKT) and dendritic (DC) cells; (ii) supporting regulation of FOXP3 + T cells (Treg); and (iii) promoting M2 activated macrophage polarization.…”

Section: Nanomedicines For Targeting Tme: Application Of Natural and ...mentioning

confidence: 99%

Biomaterial-Based Responsive Nanomedicines for Targeting Solid Tumor Microenvironments

Avgoustakis,

Angelopoulou

2024

Pharmaceutics

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Solid tumors are composed of a highly complex and heterogenic microenvironment, with increasing metabolic status. This environment plays a crucial role in the clinical therapeutic outcome of conventional treatments and innovative antitumor nanomedicines. Scientists have devoted great efforts to conquering the challenges of the tumor microenvironment (TME), in respect of effective drug accumulation and activity at the tumor site. The main focus is to overcome the obstacles of abnormal vasculature, dense stroma, extracellular matrix, hypoxia, and pH gradient acidosis. In this endeavor, nanomedicines that are targeting distinct features of TME have flourished; these aim to increase site specificity and achieve deep tumor penetration. Recently, research efforts have focused on the immune reprograming of TME in order to promote suppression of cancer stem cells and prevention of metastasis. Thereby, several nanomedicine therapeutics which have shown promise in preclinical studies have entered clinical trials or are already in clinical practice. Various novel strategies were employed in preclinical studies and clinical trials. Among them, nanomedicines based on biomaterials show great promise in improving the therapeutic efficacy, reducing side effects, and promoting synergistic activity for TME responsive targeting. In this review, we focused on the targeting mechanisms of nanomedicines in response to the microenvironment of solid tumors. We describe responsive nanomedicines which take advantage of biomaterials’ properties to exploit the features of TME or overcome the obstacles posed by TME. The development of such systems has significantly advanced the application of biomaterials in combinational therapies and in immunotherapies for improved anticancer effectiveness.

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Section: Nanomedicines For Targeting Tme: Application Of Natural and ...mentioning

confidence: 99%

Biomaterial-Based Responsive Nanomedicines for Targeting Solid Tumor Microenvironments

Avgoustakis,

Angelopoulou

2024

Pharmaceutics

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“…“Earlier” lactate is considered a by-product of enhanced aerobic glycolysis and accumulated in malignant cells, raising the pH of the tumor microenvironment but a recent investigation by Brandon et al. suggests that it fuels the tricarboxylic acid cycle (TCA) ( 48 ). Lactate promotes HIF-1α activity by blocking the prolyl hydroxylases 2 (PDH 2).…”

Section: Hallmarks Of T-cell Malignanciesmentioning

confidence: 99%

“…Angiogenesis generation of new blood vessels in developing malignant cells in an uncontrolled manner to meet the demand for oxygen and nutrients. On the contrary, it results in some disorganized structure with branching and splitting forming a chaotic and leaky network (47). Such a clumsy structure leads to inadequate blood flow, anaerobic conditions (hypoxic environment), and the generation of free radicals.…”

Section: Tumor Microenvironment and Metabolic Alteration In Malignant...mentioning

confidence: 99%

Melatonin: a modulator in metabolic rewiring in T-cell malignancies

Rai,

Roy,

Hajam

2024

Front. Oncol.

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Melatonin, (N-acetyl-5-methoxytryptamine) an indoleamine exerts multifaced effects and regulates numerous cellular pathways and molecular targets associated with circadian rhythm, immune modulation, and seasonal reproduction including metabolic rewiring during T cell malignancy. T-cell malignancies encompass a group of hematological cancers characterized by the uncontrolled growth and proliferation of malignant T-cells. These cancer cells exhibit a distinct metabolic adaptation, a hallmark of cancer in general, as they rewire their metabolic pathways to meet the heightened energy requirements and biosynthesis necessary for malignancies is the Warburg effect, characterized by a shift towards glycolysis, even when oxygen is available. In addition, T-cell malignancies cause metabolic shift by inhibiting the enzyme pyruvate Dehydrogenase Kinase (PDK) which in turn results in increased acetyl CoA enzyme production and cellular glycolytic activity. Further, melatonin plays a modulatory role in the expression of essential transporters (Glut1, Glut2) responsible for nutrient uptake and metabolic rewiring, such as glucose and amino acid transporters in T-cells. This modulation significantly impacts the metabolic profile of T-cells, consequently affecting their differentiation. Furthermore, melatonin has been found to regulate the expression of critical signaling molecules involved in T-cell activations, such as CD38, and CD69. These molecules are integral to T-cell adhesion, signaling, and activation. This review aims to provide insights into the mechanism of melatonin’s anticancer properties concerning metabolic rewiring during T-cell malignancy. The present review encompasses the involvement of oncogenic factors, the tumor microenvironment and metabolic alteration, hallmarks, metabolic reprogramming, and the anti-oncogenic/oncostatic impact of melatonin on various cancer cells.

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“…Therefore, lactate is effluxed out of the cell through a cell surface transporter known as MCT-4, which ultimately contributes to extracellular acidification and provides a favorable microenvironment for cellular proliferation. Henceforth, HIF-1α, through direct regulation of PDK1, LDHA, and MCT-4, effectively saves cancer cells from acidosis and harmful reactive oxygen species ( Gatenby et al, 2007 ; Pinheiro et al, 2012 ; Doherty and Cleveland, 2013 ; Singh et al, 2023 ). Past research suggests that HIF-1α dependent expression of PDK-1 is required for metastatic colonization of breast cancer cells in the liver, contrary to lung or bone metastasis ( Dupuy et al, 2015 ).…”

Section: How Do Tumor Cells Adapt Under Hypoxia?mentioning

confidence: 99%

NF-κB mediated regulation of tumor cell proliferation in hypoxic microenvironment

et al. 2023

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Hypoxia is caused by a cancer-promoting milieu characterized by persistent inflammation. NF-κB and HIF-1α are critical participants in this transition. Tumor development and maintenance are aided by NF-κB, while cellular proliferation and adaptability to angiogenic signals are aided by HIF-1α. Prolyl hydroxylase-2 (PHD-2) has been hypothesized to be the key oxygen-dependent regulator of HIF-1α and NF-transcriptional B’s activity. Without low oxygen levels, HIF-1α is degraded by the proteasome in a process dependent on oxygen and 2-oxoglutarate. As opposed to the normal NF-κB activation route, where NF-κB is deactivated by PHD-2-mediated hydroxylation of IKK, this method actually activates NF-κB. HIF-1α is protected from degradation by proteasomes in hypoxic cells, where it then activates transcription factors involved in cellular metastasis and angiogenesis. The Pasteur phenomenon causes lactate to build up inside the hypoxic cells. As part of a process known as lactate shuttle, MCT-1 and MCT-4 cells help deliver lactate from the blood to neighboring, non-hypoxic tumour cells. Non-hypoxic tumour cells use lactate, which is converted to pyruvate, as fuel for oxidative phosphorylation. OXOPHOS cancer cells are characterized by a metabolic switch from glucose-facilitated oxidative phosphorylation to lactate-facilitated oxidative phosphorylation. Although PHD-2 was found in OXOPHOS cells. There is no clear explanation for the presence of NF-kappa B activity. The accumulation of the competitive inhibitor of 2-oxo-glutarate, pyruvate, in non-hypoxic tumour cells is well established. So, we conclude that PHD-2 is inactive in non-hypoxic tumour cells due to pyruvate-mediated competitive suppression of 2-oxo-glutarate. This results in canonical activation of NF-κB. In non-hypoxic tumour cells, 2-oxoglutarate serves as a limiting factor, rendering PHD-2 inactive. However, FIH prevents HIF-1α from engaging in its transcriptional actions. Using the existing scientific literature, we conclude in this study that NF-κB is the major regulator of tumour cell growth and proliferation via pyruvate-mediated competitive inhibition of PHD-2.

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Hypoxia induced lactate acidosis modulates tumor microenvironment and lipid reprogramming to sustain the cancer cell survival

Cited by 15 publications

References 113 publications

Biomaterial-Based Responsive Nanomedicines for Targeting Solid Tumor Microenvironments

Biomaterial-Based Responsive Nanomedicines for Targeting Solid Tumor Microenvironments

Melatonin: a modulator in metabolic rewiring in T-cell malignancies

NF-κB mediated regulation of tumor cell proliferation in hypoxic microenvironment

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