Page 189 - EJMO-9-1

Eurasian Journal of Medicine and
Oncology
Research on hypoxia and ECM in cancer

whereas upregulation of miR-200 can partially reverse this pathway. The inhibition of LPA1 or the use of the tyrosine
process. MiR-200 targets Fli-1 and TCF12, regulating the kinase inhibitor nintedanib can suppress invadopodia
expression of fibronectin (FN) and lysyl oxidase, thereby formation, indicating that the LPA1 and PDGFR-Akt
promoting ECM remodeling and facilitating cancer cell signaling axis could serve as potential therapeutic targets. 70
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invasion and metastasis. Qiu et al. identified FPC@S, a The ECM is a non-cellular, yet physiologically active
photodynamic immunomodulator targeting CAF-derived component of tissue that provides structural support
ECM, to enhance photodynamic immunotherapy for and facilitates cell communication, adhesion, and
breast cancer. FPC@S combines an ECM-targeting proliferation. The alignment of ECM fibers significantly
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peptide, a photosensitizer, and an anti-fibrotic agent to affects breast cancer metabolism and EMT, with aligned
generate ROS, remodel the ECM, and kill cancer cells fibers enhancing glycolytic activity and promoting the
while releasing SIS3 to inhibit CAF activity, reduce fibrosis, progression to a metastatic phenotype, particularly in
and prevent metastasis. In addition, ROS enhances the breast cancer subsets with high collagen remodeling.
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tumor vasculature to improve drug and immune cell Metabolic reprogramming, one of the cancer hallmarks,
penetration. When combined with immune checkpoint is related to cancer initiation and progression. Cancer
inhibitors, FPC@S effectively suppresses both primary metabolism is altered in response to TME, and aerobic
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and metastatic tumors. De Vita et al. developed a glycolysis (Warburg effect) is the major pathway to produce
nanotherapeutic agent targeting the ECM by conjugating ATP, while cells rely primarily on mitochondrial oxidative
lysyl oxidase 1 (LOX) inhibitors to lipid NPs, preventing phosphorylation. Cancer cells also exhibit alterations in
the crosslinking of elastin and collagen fibers. When other metabolic pathways, such as increased glutamine
these NPs are loaded with the chemotherapeutic agent metabolism and altered mitochondrial function to help
epirubicin, they significantly inhibit the growth of TNBC cancer cells adapt to the unique metabolic demands of the
cells and demonstrate extended survival, reduced toxicity, TME and support their survival and growth. Tennant
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and higher biocompatibility in vivo. This multifunctional et al. discovered that metabolic pathways observed in
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nanotherapeutic agent holds promise as a new strategy for tumors differ from those originating in normal tissues,
TNBC treatment. 63 enabling cancer cells to adapt to increased metabolic
3.6.5. Multiple biological processes caused by hypoxia demands and TME changes. Cancer cells elevate rates of
(red) glucose and glutamine metabolism to meet bioenergetic
and synthetic demands. These changes are driven by
“Hypoxia” and “angiogenesis” are the most frequently alterations in signaling pathways involving PI3K, mTOR,
mentioned nodes in this cluster, as they are critical HIFs, and transcription factors. Meanwhile, the Warburg
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conditions for the growth of solid tumors. There is a effect in cancer cells, marked by increased glycolysis, is
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strong interconnection between tumor angiogenesis, orchestrated by mitochondrial alterations, upregulation
hypoxia, and TME, which together drive tumor initiation of glycolytic enzymes, pH regulation, hypoxia-induced
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and progression. Under hypoxic conditions, HIF-1α metabolic shifts, and p53 dysfunction. Key transcription
binds to the HIF-1β subunit to form a dimer, activating factors c-MYC, HIF-1, and p53 play pivotal roles in
the expression of target genes involved in cell proliferation, metabolic reprogramming. Simultaneously, lactate,
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metabolism, angiogenesis, cancer immune response, and the glycolysis product, impacts endothelial cells directly
treatment resistance. 66-68 Zhang et al. discovered that through MCT-1 entry, activating the NF-κB/IL-8 pathway
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hypoxia and low glucose levels coexist in small bowel and promoting angiogenesis through cell migration
vascular malformation disease (SBVM), synergistically and tube formation. Végran et al. discovered that this
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enhancing angiogenesis. Mechanistically, these conditions signaling mechanism involves prolyl-hydroxylase and
promote angiogenesis by activating the transcription of ROS integration. In mouse models, MCT4-mediated
the long non-coding RNA HGDILnc1. HGDILnc1 inhibits lactate release stimulates IL-8-dependent angiogenesis and
SUMOylation-induced ubiquitination of ENO1 and tumor growth, emphasizing a crucial connection between
activates ALDOC transcription, driving both glycolysis tumor metabolism and angiogenesis mediated by lactate
and angiogenesis. HGDILnc1 is highly expressed in SBVM signaling in endothelial cells. Furthermore, Ciavardelli
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tissues and displays a positive correlation with NeuroD1, et al. discovered that BCSCs undergo a metabolic shift
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ENO1, and ALDOC. Moreover, research by Lebel et al. toward glycolysis compared to differentiated cancer cells,
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identified pulmonary parenchymal hypoxia as a key feature exhibiting increased activity in key enzymes of anaerobic
of idiopathic pulmonary fibrosis. Hypoxia enhances lung glucose metabolism and altered redox status. Inhibiting
fibrosis by promoting the formation of invadopodia in lung glycolysis with 2-deoxyglucose not only hinders BCSC
fibroblasts through an LPA1 receptor-dependent signaling proliferation but also synergistically enhances the efficacy

Volume 9 Issue 1 (2025) 181 doi: 10.36922/ejmo.7116