Page 193 - EJMO-9-1

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

and Mironchik Y. have also become increasingly active in This ECM degradation creates a self-reinforcing cycle,
recent years, deepening their research in this area. The top allowing better penetration of both BM/LPsiTGF-β NPs
10 journals by publication volume account for 71 articles, and CAR-T cells into the tumor, ultimately improving
representing 20.22% of the total output. “Cancer” is the CAR-T cell efficacy in treating TNBC. 94
most prolific journal, while the “International Journal of
Molecular Sciences” holds the highest citation frequency. 4.2. Pancreatic cancer
The TME plays a significant role in cancer, and it The interplay between desmoplasia and hypoxia in pancreatic
encompasses pH levels, oxygen levels, ECM, connective cancer creates a tumor-supportive microenvironment.
tissue, and tumor vasculature, among others. The ECM, Studies have demonstrated that hypoxic pancreatic stellate
6
comprising about 300 proteins, intricately regulates cellular cells (PSCs) promote cancer cell motility by altering ECM
processes, provides a structural foundation for tissues, fiber structure. Under hypoxic conditions, PSCs produce
and contributes to tumor invasion and metastasis. 7-10 The a highly ordered parallel fiber structure in the 3D matrix,
key terms “tumor microenvironment” and “extracellular inducing directed migration of cancer cells. Gene analysis
matrix” are drawing attention in hypoxia and breast reveals that the PLOD2 gene regulates ECM fiber structure
cancer research, and mounting evidence highlights in PSCs. Knockdown of PLOD2 disrupts the parallel fiber
their influence on breast cancer progression, specifically structure of the 3D matrix, resulting in reduced directed
in shaping cellular metabolism and fostering tumor migration of cancer cells. This indicates that hypoxia-
metastasis. 91,92 induced PLOD2 expression promotes pancreatic cancer cell
migration by modulating ECM structure. In pancreatic
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From the keyword analysis, the most frequently ductal adenocarcinoma (PDA), ECM deposition supports
mentioned cancers include breast cancer, lung cancer, cancer cell survival while also inhibiting tumor growth
pancreatic cancer, glioblastoma multiforme (GBM), liver through oxidative stress. The protein fibulin-5 (Fbln5)
cancer, squamous cell carcinoma, prostate cancer, and limits ROS production by blocking ECM signaling,
colorectal cancer. This highlights the significant role of thereby supporting PDA progression. Topalovski et
hypoxia and ECM across a wide range of cancers. al. 6found that hypoxia induces Fbln5 expression through
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the TGF-β and PI3K pathways. Inhibiting these pathways
4.1. Breast cancer
reduces Fbln5 production, offering a potential strategy
The TME plays a critical role in facilitating the adaptation for suppressing PDA progression. The poor response
96
of breast cancer cells to hypoxic conditions and promoting of pancreatic cancer to immunotherapy is largely due
their migration and invasion. Breast cancer cells engage to its immunosuppressive microenvironment. Li et al.
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integrin αvβ3 with platelet adhesive proteins to sustain discovered that tumor-secreted oncogenic collagen
mTOR activation under hypoxia, thereby alleviating the exacerbates immunosuppression and diminishes the
inhibition of protein synthesis and enhancing invasiveness. effectiveness of immunotherapy. They developed a nano-
This suggests that the interaction between specific ECM drug-bacteria conjugate capable of penetrating the dense
proteins and integrins can hyperactivate mTOR, thereby fibrotic stroma surrounding pancreatic tumors, depleting
boosting cancer cell invasion and metastasis under oncogenic collagen, and blocking the FAK/MAPK/AKT
hypoxic conditions. Qiu et al. have developed FPC@S, signaling pathways. This approach enhances the efficacy
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a photodynamic immunomodulator that targets the ECM of immune checkpoint inhibition therapy. The study
of breast cancer. It remodels the ECM by generating ROS, underscores the critical role of oncogenic collagen in poor
kills cancer cells, and releases SIS3 to inhibit the activity therapeutic outcomes in pancreatic cancer and introduces
of CAFs, reducing fibrosis and metastasis. This approach a targeted therapeutic platform to improve pancreatic
improves drug and immune cell penetration, enhances cancer immunotherapy. 97
the efficacy of immunotherapy, and effectively suppresses
both primary and metastatic tumors. While CAR-T cells 4.3. Lung cancer
62
have demonstrated remarkable efficacy in hematological TGF-β and persistent hypoxia synergistically influence
cancers, their success in solid tumors has been limited. To the TME, leading to ECM abnormalities and EMT. Ando
enhance CAR-T cell activity in solid tumors, Lv et al. have et al. revealed that stable HIF-1α expression regulates the
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developed BM/LPsiTGF-β NPs. These NPs deliver TGF-β dissociation of the E-cadherin/β-catenin complex through
siRNA and the nanozyme MnO , which work together protein phosphatase activity, thereby inhibiting TGF-β-
2
to remodel the TME. BM/LPsiTGF-β NPs downregulate induced EMT. The inhibition of protein phosphatase 2A
TGF-β to degrade the ECM and generate O to reduce activity can reverse the suppression of TGF-β-induced
2
HIF-α, thereby alleviating tumor immunosuppression. EMT by HIF-1α. This study is the first to demonstrate
Volume 9 Issue 1 (2025) 185 doi: 10.36922/ejmo.7116