Page 190 - EJMO-9-1

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

of doxorubicin. In addition, Sullivan et al. found that conditions by inducing P4HA1, P4HA2, and PLOD2
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hypoxia-induced chemoresistance in breast carcinoma expression in fibroblasts” (global citations = 369; local
cells shifts toward drug-induced senescence rather than citations = 27), and “Procollagen lysyl hydroxylase 2 is
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apoptosis or mitotic catastrophe. Targeting HIF-1α essential for hypoxia-induced breast cancer metastasis”
prevents hypoxia-induced resistance by restoring drug- (global citations = 191; local citations = 16). Among
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induced senescence, highlighting the role of HIF-1 the top 10 highly cited papers, Ju et al.’s 2017 paper,
in mediating adaptations leading to drug resistance. “Hypoxia selectively enhances integrin α5β1 receptor
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Cancer cells adapt to increased metabolic demands by expression in breast cancer to promote metastasis,” has
upregulating glucose transport and glycolysis, even in the highest local citations/global citations ratio, reaching
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the presence of oxygen, while suppressing mitochondrial 12.64%. This is followed by Gilkes et al.’s 2013 paper,
respiration to evade apoptosis. 77,78 Hypoxia-induced “Procollagen lysyl hydroxylase 2 is essential for hypoxia-
metabolism generates ROS, which is countered by induced breast cancer metastasis” (local citations = 16;
increased NADPH from upregulated glycolysis, thereby global citations = 191), and another 2013 paper by Gilkes
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maintaining redox balance. 79,80 PKM2, a glycolytic enzyme, et al., “Hypoxia-inducible factor 1 (HIF-1) promotes
and ROS form a negative feedback loop, regulated by extracellular matrix remodeling under hypoxic conditions
HIF-1α and MYC, which activates glycolytic enzymes and by inducing P4HA1, P4HA2, and PLOD2 expression in
suppresses oxidative phosphorylation, enhancing cancer fibroblasts” (local citations = 27; global citations = 369),
cell survival. 81,83 The Warburg effect increases ROS levels, with ratios of 8.38% and 7.32%, respectively. These ratios
countered by the antioxidant effects of glycolytic enzymes highlight their significant recognition and impact within
and NADPH1. 84,85 Tumor cells exhibit both glycolytic and the field.
oxidative metabolism, conferring resistance to oxidative Nodes displaying higher intermediary centrality are
stress and regulating p53 downstream genes involved in adorned with a distinctive purple outer circle, employing
energy metabolism. 86,87 CiteSpace software for co-cited document visual analysis
Figure 6C highlights the burst detection of keywords, (Figure 7A). Cluster analysis categorizes terms within
indicating that “endothelial growth factor” was the earliest the realm of hypoxia, ECM, and cancer into 10 clusters
and longest-lasting keyword. Following that, “interstitial (Table 7), with the silhouette value (S) denoting the
fluid pressure,” “matrix metalloproteinase,” and “growth reliability of each cluster. In general, S > 0.5 indicates
factor-beta” also exhibited significant research interest, an appropriate cluster, and S > 0.7 implies a compelling
particularly between 2014 and 2020. In the past 3 years, cluster. In this study, all clusters exhibit S-values > 0.7,
the frequency of studies related to various cancers and which emphases their credibility.
associated prognostic models has increased notably. Figure 7B demonstrates that the three largest clusters are
An analysis of thematic trends (Figure 6D) reveals #0 “cancer-associated fibroblast,” #1 “tumor angiogenesis,”
that early research focused primarily on topics such as and #2 “TNBC.” Among these, cluster #1 “tumor
“endothelial growth factor,” “inducible factor-1,” “breast angiogenesis” is the earliest cluster to emerge, while clusters
cancer,” “pancreatic cancer,” “prostate cancer,” “phenotype,” #0 “cancer-associated fibroblast,” #2 “TNBC,” and #4
“NF-kappa-B,” and “matrix metalloproteinase.” By 2020, “therapy resistance” are the most recent. Nodes with high
research on gene expression related to “hypoxia” and betweenness centrality are mainly distributed in clusters #1
the “extracellular matrix” reached its peak popularity. “tumor angiogenesis,” #2 “TNBC,” and #3 “HIF,” indicating
Significant attention has also been given to studies on that these research areas play critical roles in the field.
“invasion,” “TGF-beta,” “lysyl oxidase,” “NF-kappa-B,” Figure S5 (supplementary file) displays the top 25
and “apoptosis.” In recent years, research on CAFs has references with the strongest citation bursts. The top three
gradually emerged as a new trend. are from Gilkes et al. (citation burst strength = 8.26),
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followed by Lu et al. (citation burst strength = 5.37), and
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3.7. Cited and co-cited references analysis Gilkes et al. (citation burst strength = 4.25). The burst
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Table 6 lists the top 10 most highly cited papers. The top duration for these top 25 references predominantly spans
three most-cited papers are all collaborations between over 2 years, highlighting their sustained impact across
Semenza G.L., Wirtz D., and Gilkes D.M. These include various phases of research.
the 2014 paper “Hypoxia and the extracellular matrix:
drivers of tumor metastasis” (global citations = 1035; local 4. Discussion
citations = 44), the 2013 paper “Hypoxia-inducible factor The study employed a bibliometric approach for objective
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1 (HIF-1) promotes ECM remodeling under hypoxic analysis to comprehensively assess the current state,

Volume 9 Issue 1 (2025) 182 doi: 10.36922/ejmo.7116