EFFECT OF HYPOXIA ON MICROENVIRONMENT FACTORS OF GASTRIC CANCER AND RELATIONSHIP WITH CLINICAL OUTCOME

Authors

  • L. Bubnovskaya R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, the National Academy of Sciences of Ukraine, Kyiv, Ukraine
  • I. Ganusevich R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, the National Academy of Sciences of Ukraine, Kyiv, Ukraine
  • S. Merentsev City Clinical Oncological Center, Kyiv, Ukraine
  • D. Osinsky City Clinical Oncological Center, Kyiv, Ukraine

DOI:

https://doi.org/10.15407/exp-oncology.2025.03.267

Keywords:

gastric cancer, tumor hypoxia, factors of TME, cancer-associated adipocytes, minimal residual disease

Abstract

The tumor microenvironment (TME) plays a critical role in tumor survival, progression, and metastasis. Нypoxia level, as an integral parameter of TME, occupies a central place in the regulation and control of all events occurring in TME. The review focuses on the findings obtained by the authors during the study of the hypoxia impact on the processes related to some microenvironmental factors in order to identify its prognostic significance regarding the course of the disease. It was shown that most microenvironmental factors are largely associated with hypoxia and involved in the processes of the tumor response to therapy. Their significance in the development of minimal residual disease and in the processes that can be affected by adipose tissue is also discussed. Therapeutic strategies based on the tumor’s distinctive properties should be more highly selective in relation to the tumor, allowing the highest possible therapeutic gain for a more favorable prognosis of the disease outcome and overall survival of patients with gastric cancer. The literature data on the subject are also discussed.

References

Santucci C, Carioli G, Bertuccio P, et al. Progress in cancer mortality, incidence, and survival: a global overview. Eur J Cancer Prev. 2020;(5):367-381. https://doi.org/10.1097/CEJ.0000000000000594

hanahan d. hallmarks of cancer: new dimensions. Cancer Discov. 2022;(1):31-46. https://doi.org/10.1158/2159- 8290.Cd-21-1059

Siminzar P, Reza Tohidkia M, Eppard E, et al. Recent trends in diagnostic biomarkers of tumor microenvironment.

Mol Imaging Biol. 2023;(3):464-482. https://doi.org/10.1007/s11307-022-01795-1

Redfern A, Agarwal V, Thompson EW. hypoxia as a signal for prison breakout in cancer. Curr Opin Clin Nutr Metab Care. 2019;(4):250-263. https://doi.org/10.1097/MCO.0000000000000577

hirata y, Noorani A, Song, S. et al. Early stage gastric adenocarcinoma: clinical and molecular landscapes. Nat Rev Clin Oncol. 2023;20:453-469. https://doi.org/10.1038/s41571-023-00767-w

Sauerbrei W, Taube SE, McShane LM, et al. Reporting recommendations for tumor marker prognostic studies (REMARK): An abridged explanation and elaboration. J Natl Cancer Inst. 2018;1;110(8):803-811. https://doi. org/10.1093/jnci/djy088

Anastasiou d. Tumour microenvironment factors shaping the cancer metabolism landscape. Brit J Cancer.

;116:277-286. https://doi.org/10.1038/bjc.2016.412

Rojas A, Araya P, Gonzalez I, Morales E. Gastric tumor microenvironment. Adv Exp Med Biol. 2020;1226:23-35. https://doi.org/10.1007/978-3-030-36214-0_2

Anderson NM, Simon MC. The tumor microenvironment. Curr Biol. 2020;30(16):R921-R925. https://doi.org/ 10.1016/j.cub.2020.06.081

Wei R, Liu S, Zhang S. Cellular and extracellular components in tumor microenvironment and their application in early diagnosis of cancers. Anal Cell Pathol (Amst). 2020:6283796. https://doi.org/10.1155/2020/6283796

Vaupel P, Schmidberger h, Mayer A. The Warburg effect: essential part of metabolic reprogramming and central contributor to cancer progression. Int J Radiat Biol. 2019;95(7):912-919. https://doi.org/10.1080/09553002.2019. 1589653

Singleton dC, Macann A, Wilson WR. Therapeutic targeting of the hypoxic tumour microenvironment Nat Rev Clin Oncol. 2021;18(12):751-772. https://doi.org/10.1038/s41571-021-00539-4

Jing Z, yang f, Shao C, et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer. 2019;18(1):157. https://doi.org/10.1186/s12943-019-1089-9.

Chen P-S, Chiu W-T, hsu P-L, et al. Pathophysiological implications of hypoxia in human diseases. J Biomed Sci.

;27(1):63. https://doi.org/10.1186/s12929-020-00658-7

hao X, Ren y, feng M, et al. Metabolic reprogramming due to hypoxia in pancreatic cancer: implications for tumor for- mation, immunity, and more. Biomed Pharmacother. 2021;141:111798. https://doi.org/10.1016/j.biopha.2021.111798

horsman MR, Vaupel P. Pathophysiological basis for the formation of the tumor microenvironment. Front Oncol.

;6:66. https://doi.org/10.3389/fonc.2016.00066

Vaupel P. Pathophysiology of human tumors. In: Osinsky S, friess h, Vaupel P, eds. Tumor hypoxia in the clinical setting. Kiev, Akademperiodica, 2011:23-70. https://doi.org/10.15407/akademperiodyka.169.272

Osinsky S, Kelleher d. Tumor-host interections and the metabolic microenvironment of cancer cells. In: Osinsky S, friess h, Vaupel P, eds. Tumor hypoxia in the clinical setting. Kiev, Akademperiodica, 2011:129-153. https://doi. org/10.15407/akademperiodyka.169.272

Bubnovskaya L, Osinsky d. Tumor microenvironment and metabolic factors: contribution to gastric cancer. Exp Oncol. 2020;42(1):2-10. https://doi.org/10.32471/exp-oncology.2312-8852.vol-42-no-1.14056

hanying Zhou h, Meng Wang M, yixi Zhangy, et al. functions and clinical significance of mechanical tumor mic- roenvironment: cancer cell sensing, mechanobiology and metastasis. Cancer Commun (Lond). 2022;(5):374-400. https://doi.org/10.1002/cac2.12294

Moulder JE, Rockwell S. hypoxic fractions of solid tumour. Int J Radiat Oncol Biol Phys. 1984;10:695-712. https:// doi.org/10.1016/0360-3016(84)90301-8

Li y, Zhao L, Li Xf. hypoxia and the tumor microenvironment. Technol Cancer Res Treat. 2021:15330338211036304. https://doi.org/10.1177/15330338211036304

Sullivan R, Graham Ch. hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev.

;26(2):319-331. https://doi.org/10.1007/s10555-007-9062-2

Tao J, yang G, Zhou ZW, et al. Targeting hypoxic tumor microenvironment in pancreatic cancer. J Hematol Oncol.

;14(1):14. https://doi.org/10.1186/s13045-020-01030-w

Zhou J, Lei N, Tian W. Recent progress of the tumor microenvironmental metabolism in cervical cancer radioresis- tance. Front Oncol. 2020;12:999643. https://doi.org/10.3389/fonc.2022.999643

Luoto KR, Kumareswaran R, Bristow RG. Tumor hypoxia as a driving force in genetic instability. Genome Integr.

;4(1):5. https://doi.org/10.1186/2041-9414-4-5

Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for ef- fective therapy. Nat Med. 2018;24(5):541-550. https://doi.org/10.1038/s41591-018-0014-x

Gouel P , decazes P, Vera P. Advances in PET and MRI imaging of tumor hypoxia. Front Med (Lausanne).

;10:1055062. https://doi.org/10.3389/fmed.2023.1055062

Li L, Wei y, huang y. To explore a representative hypoxic parameter to predict the treatment response and prog- nosis obtained by [18f]fMISO-PET in patients with non-small cell lung cancer. Mol Imaging Biol. 2018;20(6):1061- 1067. https://doi.org/10.1007/s11307-018-1190-2

Evans CE, Mattock K, humphries J, et al. Techniques of assessing hypoxia at the bench and bedside. Angiogenesis.

;14(2):119-124. https://doi.org/10.1007/s10456-011-9205-5

Bubnovskaya L, Kovelskaya A, Boldeskul I, et al. Assessment of tumor hypoxia and hypoxia-relared metabolites by NMR spectroscopy and its prognostic relevance. In: Osinsky S, friess h, Vaupel P, eds. Tumor hypoxia in the clinical setting. Kiev, Akademperiodica, 2011:203-219. https://doi.org/10.15407/akademperiodyka.169.272

deng C, deng G, Chu h , et al. Construction of a hypoxia-immune-related prognostic panel based on integra- ted single-cell and bulk RNA sequencing analyses in gastric cancer. Front Immunol. 2023;14:1140328. https://doi. org/10.3389/fimmu.2023.1140328

Bubnovskaya L, Osinsky d, Trachevsky V, et al. Premorphological alterations in gastric mucosa in patients with gastric cancer: hypoxia level assessed by 31P NMR spectroscopy. Exp Oncol. 2014;36:271-275. PMId: 25537223.

Osinsky dS, Bubnovskaya LN, Kovelskaya AV, Merentsev SP. Association between hypoxia level in gastric cancer, assessed by 31P NMR spectroscopy, and results of patients treatment with different methods. Oncology. 2014;16:283- 287 (in Ukrainian).

Antonov EA, Gumenyuk Ld, Mamontova LA, Osinsky dS. Tumor cells in regional lymph nodes of patients with gastric cancer with category N0 and their clinical significance. Oncology. 2013;15(3):230-234.

Osinsky SP, Gumenyuk Ld, Osinsky dS, et al. Expression of hypoxia-inducible factor-1α in tissue of gastric cancer and its connection with some clinical characteristics of disease. Oncology. 2006;8(1):33-37 (in Russian).

Osinsky S, Bubnovskaya L, Ganusevich I, et al. hypoxia, tumor associated macrophages, microvessel density, VEGf and matrix metalloproteinases in human gastric cancer: interaction and impact on survival. Clin Transl Oncol. 2011;13(2):133-138. https://doi.org/10.1007/s12094-011-0630-0

Kovelskaya A, Gumenyuk L, Osinsky d, et al. factors of angiogenesis in human gastric cancer tissue and their clini- cal significance. Oncology. 2012;14(4):286-292 (in Ukrainian).

Merentsev SP, Lisniyak IA, Osinsky dS, Sergienko TK. Level of vascular endothelial growth factor in the blood serum of patients with gastric cancer. Oncology. 2007;9(1):21-24 (in Ukrainian).

Osinsky dS, Bubnovska LN, Kovelskaya AV, et al. Clinical and prognostic significance of hypoxia – associated tu- mor microenvironment factors. Oncologiya. 2015;3(65):162-168 (in Ukrainian).

Gumenyuk Ld, Osinsky dS, Bubnovska LN, et al. Immunohistochemical evaluation of с-MyC expression in gas- tric cancer tissue: association with microenvironment indices, disseminated tumor cellsand survival. Oncology. 2015;17(1):31-37 (in Ukrainian).

yashiro M, Kinoshita h, Tsujio G. Sdf1α/CXCR4 axis may be associated with the malignant progression of gastric cancer in the hypoxic tumor microenvironment. Oncol Lett. 2021;(1):38. https://doi.org/10.3892/ol.2020.12299

Ganusevich I, Mamontova L, Kovelskaya AV, et al. Matrix metalloproteinases as tumor stroma microenvironment factors: the role in course of minimal residual disease in gastric cancer. Oncology. 2015;3(65):169-176 (in Ukrai- nian).

Osinsky d, Kovelskaya A, Bubnovskaya L, et al. CXCR4 expression in gastric cancer and bone marrow: association with hypoxia-regulated indices, disseminated tumor cells, and patients survival. J Cancer Res. 2015;9:1-8. https:// doi.org/10.1155/2015/980214

Osinsky d, Kovelskaya A, Bubnovskaya L, et al. The relationship of tumor-infiltrating Cd8+- and Cd45RO+T- lymphocytes with the hypoxic profile of gastric cancer, disseminated tumor cells and the disease outcome. Ukr Med Chasopys. 2015;105(1):74-78.

Osinsky S, Kovelskaya A, Bubnovskaya L, et al. Cd8 and Cd45RO T lymphocytes in bone marrow of gastric cancer patients: correlation with disseminated tumor cells and disease outcome. Exp Oncol. 2015;37(1):48-52.

Bubnovskaya L, Kovelskaya A, Gumenyk L, et al. disseminated tumor cells in bone marrow of gastric can- cer patients: correlation with tumor hypoxia and clinical relevance. J Oncol. 2014;2014(1):582140. https://doi. org/10.1155/2014/582140

Trayhurn P, Wang B, Wood IS. hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity?

Br J Nutr. 2008;100(2):227-235. https://doi.org/10.1017/S0007114508971282

Munteanu R, Onaciu A, Moldovan C, et al. Adipocyte-based cell therapy in oncology: the role of cancer-associated adipocytes and their reinterpretation as delivery platforms. Pharmaceutics. 2020;12(5):402. https://doi.org/10.3390/ pharmaceutics12050402

Attané C, Milhas d, hoy AJ, Muller C. Metabolic remodeling induced by adipocytes: a new Achilles’ heel in inva- sive breast cancer? Curr Med Chem. 2020;7(24):3984-4001. https://doi.org/10.2174/0929867325666180426165001

Bubnovskaya L. Тumor microenvironment and obesity. Acta Sci Cancer Biol. 2021;5(6):5-8. https://doi.org/10.31080/ ASCB.2021.04.0307

Bubnovskaya L, Ganusevich I, Merentsev S, Osinsky d. disseminated tumor cells in bone marrow in gastric cancer patients with obesity. Cancer Stud Ther J. 2019;4(5):1-3.

Bubnovskaya L, Ganusevich I, Merentsev S, Osinsky d. Adipocytes as a risk factor for metastasis in patients with gastric cancer and normal weight. Currt Practice Med Sci. 2022;5:37-46. https://doi.org/10.9734/bpi/cpms/v5/6831f

Downloads

Published

30.12.2025

How to Cite

Bubnovskaya, L., Ganusevich, I., Merentsev, S., & Osinsky, D. (2025). EFFECT OF HYPOXIA ON MICROENVIRONMENT FACTORS OF GASTRIC CANCER AND RELATIONSHIP WITH CLINICAL OUTCOME. Experimental Oncology, 47(3), 267–276. https://doi.org/10.15407/exp-oncology.2025.03.267