Hypoxia and its importance in the course of gynaecological cancers

Hypoxia-oxygen deficiency is a feature of most solid malignant tumours. This leads to the selection of an aggressive neoplasm phenotype by activating molecular factors including hypoxia inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF) promoting angiogenesis, and also by the influence of the tumour microenvironment, no possibility of fixation of DNA damage after radio- and chemotherapy, and the change in cadherin activity. Another mechanism of hypoxia facilitates the survival, and activity of cancer stem cells (CSCs). The described therapies eliminating hypoxia include the use of cytotoxins, anaerobic bacteria, YC-1 factor, arsenic trioxide (As2O3), and eradication of CSCs by using retinoic and ursolic acid. The paper describes hypoxia as the cause of failure in the treatment of gynaecological cancers and therapies eliminating it.

Hypoxia–oxygen deficiency; Angiogenesis; Gynaecological cancers

[1] Graham K., Unger E.: “Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment”. Int. J. Nanomedicine, 2018, 13, 6049.

[2] Zhang K., Kong X., Feng G., Xiang W., Chen L., Yang F., et al.: “Investigation of hypoxia networks in ovarian cancer via bioinformatics analysis”. J Ovarian Res., 2018, 11, 16.

[3] Daskalaki I., Gkikas I., Tavernarakis N.: “Hypoxia and selective autophagy in cancer development and therapy”. Front Cell Dev. Biol., 2018, 6, 104.

[4] Yeh J.J., Kim W.Y.: “Targeting tumor hypoxia with hypoxia-activated prodrugs”. J. Clin. Oncol., 2015, 33, 1505.

[5] Seeber L.M., Horrée N., Vooijs M.A., Heintz A.P., Van der Wall E., Verheijen R.H., Van Diest P.J.: “The role of hypoxia inducible factor-1alpha in gynecological cancer”. Crit. Rev. Oncol. Hematol., 2011, 78, 173.

[6] Schito L., Semenza GL.: “Hypoxia-inducible factors: master regulators of cancer progression”. Trends Cancer, 2016, 2, 758.

[7] Choi K.S., Bae M.K., Jeong J.W., Moon H.E., Kim K.W.: “Hypoxiainduced angiogenesis during carcinogenesis”. J. Biochem. Mol. Biol. 2003, 36, 120.

[8] Shimogai R., Kigawa J., Itamochi H., Iba T., Kanamori T., Oishi M., et al.: “Expression of hypoxia-inducible factor 1alpha gene affects the outcome in patients with ovarian cancer”. Int. J. Gynecol. Cancer, 2008, 18, 499.

[9] Vordermark D., Brown J.M.: “Endogenous markers of tumor hypoxia predictors of clinical radiation resistance?”. Strahlenther Onkol., 2003, 179, 801.

[10] Lam S.W., Nota N.M., Jager A., Bos M.M., Van den Bosch J., Van der Velden A., et al.: “Angiogenesis- and hypoxia-associated proteins as early indicators of the outcome in patients with metastatic breast cancer given first-line Bevacizumab-based therapy”. Clin. Cancer Res., 2016, 22, 1611.

[11] Duechler M., Peczek L., Szubert M., Suzin J.: “Influence of hypoxia inducible factors on the immune microenvironment in ovarian cancer”. Anticancer Res., 2014, 34, 2811

[12] Jahanban-Esfahlan R., de la Guardia M., Ahmadi D., Yousefi B.: “Modulating tumor hypoxia by nanomedicine for effective cancer therapy”. J. Cell. Physiol., 2018, 233, 2019.

[13] Kelly N.J., Varga J.F.A., Specker E.J., Romeo C.M., Coomber B.L., Uniacke J., et al.: “Hypoxia activates cadherin-22 synthesis via eIF4E2 to drive cancer cell migration, invasion and adhesion”. Oncogene, 2018, 37, 651.

[14] Seo E.J., Kim D.K., Jang I.H., Choi E.J., Shin S.H., Lee S.I., et al.: “Hypoxia-NOTCH1-SOX2 signaling is important for maintaining cancer stem cells in ovarian cancer”. Oncotarget, 2016, 7, 55624.

[15] Conley S.J., Gheordunescu E., Kakarala P., Newman B., Korkaya H., Heath A.N., et al.: “Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia”. Proc. Natl. Acad. Sci.U S A, 2012, 109, 2784.

[16] Najafi M., Farhood B., Mortezaee K.: “Cancer stem cells (CSCs) in cancer progression and therapy”. J. Cell. Physiol., 2019, 234, 8381.

[17] Shen W.C., Liang C.J., Huang T.M., Liu C.W., Wang S.H., Young G.H., et al.: “Indoxyl sulfate enhances IL-1β-induced E-selectin expression in endothelial cells in acute kidney injury by the ROS/MAPKs/NFκB/AP-1 pathway”. Arch. Toxicol., 2016, 90, 2779.

[18] Pansare V., Munkarah A.R., Schimp V., Arabi M.H., Saed G.M., Morris RT., et al.: “Increased expression of hypoxia-inducible factor 1alpha in type I and type II endometrial carcinomas”. Mod. Pathol., 2007, 20, 35.

[19] Huang L., Ao Q., Zhang Q., Yang X., Xing H., Li F., et al.: “Hypoxia induced paclitaxel resistance in human ovarian cancers via hypoxiainducible factor 1alpha”. J. Cancer Res. Clin. Oncol., 2010, 136, 447.

[20] Serocki M., Bartoszewska S., Janaszak-Jasiecka A., Ochocka R.J., Collawn J.F., Bartoszewski R.: “miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target”. Angiogenesis, 2018, 21, 183.

[21] Rischin D., Peters L.J., O’Sullivan B., Giralt J., Fisher R., et al.: “Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group”. J. Clin. Oncol., 2010, 28, 2989.

[22] Nozawa-Suzuki N., Nagasawa H., Ohnishi K., Morishige K.: “The inhibitory effect of hypoxic cytotoxin on the expansion of cancer stem cells in ovarian cancer”. Biochem. Biophys. Res. Commun., 2015, 457, 706.

[23] Liu S.C., Minton N.P., Giaccia A.J., Brown J.M.: “Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis”. Gene. Ther., 2002, 9, 291.

[24] Manoochehri Khoshinani H., Afshar S., Najafi R.: “Hypoxia: A Double-Edged Sword in Cancer Therapy”. Cancer Invest., 2016, 34, 536.

[25] Casagrande F., Cocco E., Bellone S., Richter CE., Bellone M., Todeschimi P., et al.: “Eradication of chemotherapy-resistant CD44+ human ovarian cancer stem cells in mice by intraperitoneal administration of Clostridium perfringens enterotoxin”. Cancer, 2011, 117, 5519.

[26] Yeo E.J., Chun Y.S., Cho Y.S., Kim J., Lee J.C., Kim M.S., Park J.W.: “YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1”. J. Natl. Cancer Inst., 2003, 95, 516.

[27] Luo D., Zhang X., Du R., Gao W., Luo N., Zhao S., et al.: “Low dosage of arsenic trioxide (As2O3) inhibits angiogenesis in epithelial ovarian cancer without cell apoptosis”. J. Biol. Inorg. Chem., 2018, 23, 939.

[28] Cook K.M., Figg W.D.: “Angiogenesis inhibitors: current strategies and future prospects”. CA Cancer J. Clin., 2010, 60, 222.

[29] Markowska A., Jaszczyńska-Nowinka K., Kaysiewicz J., Makówka A., Markowska J.: “Angiogenesis in gynecologic malignancies”. Curr. Gynecol. Oncol., 2015, 13, 256.

[30] Januchowski R., Wojtowicz K., Zabel M.: “The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance”. Biomed. Pharmacother., 2013, 67, 669.

[31] Moreb J.S., Ucar-Bilyeu D.A., Khan A.: “Use of retinoic acid/aldehyde dehydrogenase pathway as potential targeted therapy against cancer stem cells”. Cancer Chemother. Pharmacol., 2017, 79, 295.

[32] Shah M.M., Landen C.N.: “Ovarian cancer stem cells: are they real and why are they important?” Gynecol. Oncol., 2014, 132, 483.

[33] Tong W.W., Tong G.H., Liu Y.: “Cancer stem cells and hypoxia-inducible factors (Review).” Int. J. Oncol., 2018, 53, 469.

[34] Wang W., Zhao C., Jou D., Lü J., Zhang C., Lin L., Lin J.: “Ursolic acid inhibits the growth of colon cancer-initiating cells by targeting STAT3”. Anticancer Res., 2013, 33, 4279.

[35] Owen J., McEwan., Nesbitt., Bovornchutichai P., Averre R., Borden M., et al.: “Reducing tumour hypoxia via oral administration of oxygen nanobubbles”. PLoS One, 2016, 11, e0168088.