IMR Press / EJGO / Volume 40 / Issue 5 / DOI: 10.12892/ejgo5111.2019
Open Access Review
Hypoxia and its importance in the course of gynaecological cancers
Show Less
1 Department of Perinatology and women's Diseases, Poznan University of Medical Sciences, Poland
2 Department of Oncology, Poznan University of Medical Sciences, Poland
3 Faculty of Chemistry, Adam Mickiewicz University, Poznan, Poland
4 Department of Gynecology Oncology, Center of Oncology M. Sklodowska-Curie Institute, Cracow Branch, Poland
5 Swedish Orphan Biovitrum Ltd., warsaw, Poland
Eur. J. Gynaecol. Oncol. 2019, 40(5), 711–713;
Published: 10 October 2019

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
Gynaecological cancers

Hypoxia-oxygen deficiency indicates reduced oxygen availability in tissues (~ ≤ 2% O2), which is a common feature of most solid tumours. It arises from an insufficient supply of oxygen through the vascular system in the growing tumour, which does not keep pace with rapidly proliferating tumour cells [1-4].

Blood vessels in the tumour are characterised by many abnormalities: they are widened, winding, dead-end, show increased permeability due to the lack of continuity of coverage with pericytes, and often their wall integrates with tumour cells [1,4].

Hypoxia in the tumour leads to the selection of an aggressive phenotype facilitating invasion and metastasis, which is associated with poor clinical course [2,4-6].

Mechanisms of hypoxia include: 1) increase in hypoxia inducible factor 1α (HIF-1α) protein expression, which under hypoxia conditions is not degraded in proteasomes, but penetrates into the nucleus of the cell and connects to the β subunit. The resulting heterodimer binds to the hypoxia response element (HRE) genes and regulates the expression of over 30 hypoxia-related genes, including glucose transporter-1 (GLUT-1), carbonic anhydrase 9 (CA-9), aldehyde dehydrogenase 1 (ALDH1). They are associated with unfavourable prognosis in many cancers [3,7-10]. 2) Promoting angiogenesis, a key process in tumour growth and its progression mainly by vascular endothelial growth factor (VEGF), the main stimulator of angiogenesis [6-8]. 3) Reconstruction of the intracellular matrix and immunological suppression by influencing the microenvironment [4,6,11]. 4) Resistance to radiotherapy and chemotherapy due to lack of fixation of DNA damage due to lack of oxygen and autophagy (removal of damaged cellular parts) also associated with resistance to chemotherapy [1,4,12]. 5) Influence on cadherins-adhesion molecules, which is associated with the migration of cancer cells, invasive activity, and metastasis [13]. 6) Persistence and activity of CSCs and stimulation of pathways associated with their presence (Wnt, PI-3K-Act, Hedgehog, Notch) [6,14-16].

Hypoxia is therefore an important event in carcinogenesis, including “gynaecological” cancers. Increased invasiveness, metastasis, and recurrence, included in ovarian and cervical cancer, cause an unfavourable course of the disease, which is expressed by shortened time to progression: progression free survival (PFS) and shorter overall survival (OS) [5]. Shen et al. [17] noted shortening of OS in ovarian cancer in cases of HIF-1α and VEGF expression; and they believe that these are important prognostic factors of the disease. Panasare et al. [18] found that the expression of HIF-1α plays a role in type I endometrial cancer; it correlates with the degree of histological differentiation (G), depth of invasion in myometrium, and in the degree of clinical advancement. Research by Shimogai et al. [8] in women with ovarian cancer determined that OS was shorter in cases with high HIF-1α expression, but this did not affect PFS. According to Huang et al. [19], HIF-1α expression plays a role in paclitaxel resistance, and the elimination of hypoxia, including silencing of HIF-1α by small interfering RNA (siRNA) may lead to beneficial therapeutic results. About 40 miRNAs (non-coding RNAs consisting of 19-21 nucleotides) have been identified that modify HIF-1α. Several of them, including miR-155 and miR-429, induced by hypoxia, reduce HIF-1α levels [6]. The review of Serocki et al. [20] describes many miRNAs that play a role in the regulation of hypoxia. When using them, target therapy against hypoxia, including against HIF-1α, is considered.

Many therapies that eliminate hypoxia as the cause of failure of oncological therapies are described: 1) Hypoxia-specific cytotoxins, e.g. tirapazamine, which, when used in combination with radio-and chemotherapy in studies of phase III in patients with head and neck cancer, did not show the expected clinical effectiveness [21]. The tirapazamine analogue TX-402, which is a prodrug, exerted suppressive inhibitory effect (dose-dependent) on both HIF-1α and angiogenesis in serous ovarian cancer cells. The research also showed that the expression of ovarian cancer stem cells Oct 4, Nanog, SOX2, CD133, and CD44 and hypoxia-induced Lin was inhibited by TX-402 [22]. 2) It has been shown that genetically modified anaerobic bacteria (Clostridium sporogenes) [23,24] in the animal model have a greater antineoplastic potential than the maximum doses of fluorouracil (Fu) [23]. Subsequent studies have shown on ovarian cancer cell lines that Clostridium perfringens enterotoxin eradicates CD44+ ovarian cancer stem cells that are responsible for resistance to chemotherapy [25]. 3) HIF-1α was blocked using YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole), a factor inhibiting vasoconstriction and platelet aggregation on an animal model. An inhibitory effect on tumour growth and blocking angiogenesis has been described [26]. 3) Inhibition of hypoxia-induced angiogenesis using small doses of arsenic trioxide (As2O3). It has been shown in the studies of the established ovarian cancer cell lines that added As2O3 reduces the expression of VEGFA and VEGFR2 receptor by inhibiting the VEGFA-VEGFR2-PI3K/ERK signalling pathway, which prevents tumour angiogenesis in the treatment of numerous cancers, including the treatment of gynaecological cancer [27-29]. However, there are doubts regarding the effectiveness of anti-angiogenic therapies. Conley et al. [15] hypothesized that inhibitors of angiogenesis in breast cancer induce hypoxia, resulting in an increase in CSCs, which is associated with tumour growth and metastasis. Therefore, an antineoplastic therapy would require comprehensive therapies, including against CSCs. 4) Aldehydedehydrogenase 1 (ALDH1) is a recognized marker of many cancer stem cells, including ovarian cancer. Excessive activity of this enzyme is associated with chemoresistance, and correlates with shorter PFS and OS. It has been shown that currently used chemotherapy regimens eradicate most of the tumor mass but are not effective against CSCs [30]. Moreb et al. [31] studies showed that the use of retinoic acid appears to be effective in destroying CSCs with the ALDH1 marker. 5) It has been demonstrated that CSCs -a small population of cells constituting 2-5% of the tumour mass -as well as some pathways which they use for self-renewal and survival, are associated with hypoxia [16,32,33]. Seo et al. [14] reported that hypoxia in ovarian cancer stimulates the expression of transcription factors -OCT4 and SOX2 related to self-renewal of CSCs and the Notch pathway, which controls their survival. Furthermore, SOX2 increases the resistance of CSCs by activating the expression of ABCB1 and ABCG2 membrane transporters associated with multidrug resistance. The authors also showed on the OVCAR-3 ovarian carcinoma cell lines that the use of DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester), especially with paclitaxel, fights efficiently hypoxia and has a suppressive effect on the NOTCH-1-SOX2 axis. Wang et al. [34] demonstrated that ursolic acid inhibits proliferation and reverses drug resistance of ovarian CSCs by inhibiting expression and decreasing HIF-1α and ABCG2 levels.

In summary, hypoxia is associated with the activation of many molecular factors associated with resistance to the treatment, resulting in poor clinical outcome. A variety of therapeutic attempts have been used to avoid hypoxia -as described above. Studies on animal models have demonstrated the possibility of modulating hypoxia through the use of novel oxygen-containing nanosystems allowing the normalisation of blood vessels and reoxygenation therapy [12,35]. Moreover, in recent years it has been shown that the mechanism of development and course of cancer depends on so many factors that oncological therapies require the simultaneous use of many drugs: cytostatics, immunological, anti-angiogenic, and eradicating CSCs.

Graham K., Unger E.: “Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment”. Int. J. Nanomedicine, 2018,13, 6049. 10.2147/IJN.S14046230323592
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. 10.1186/s13048-018-0388-x29482638
Daskalaki I., Gkikas I., Tavernarakis N.: “Hypoxia and selective autophagy in cancer development and therapy”. Front Cell Dev. Biol., 2018,6, 104. 30250843
Yeh J.J., Kim W.Y.: “Targeting tumor hypoxia with hypoxia-activated prodrugs”. J. Clin. Oncol., 2015,33, 1505. 10.1200/JCO.2014.60.075925800764
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. 20627616
Schito L., Semenza GL.: “Hypoxia-inducible factors: master regulators of cancer progression”. Trends Cancer, 2016,2, 758. 10.1016/j.trecan.2016.10.01628741521
Choi K.S., Bae M.K., Jeong J.W., Moon H.E., Kim K.W.: “Hypoxia-induced angiogenesis during carcinogenesis”. J. Biochem. Mol. Biol. 2003,36, 120. 12542982
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.
Vordermark D., Brown J.M.: “Endogenous markers of tumor hypoxia predictors of clinical radiation resistance?”. Strahlenther Onkol., 2003,179, 801. 10.1007/s00066-003-1150-9ca4c860f-b2eb-4130-b1f4-13583a2529ff
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. 26823602
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 23de0628-56c6-475e-90a1-2842ecb1f41bWOS:000336875200016
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. 28198007
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. 10.1038/onc.2017.37228991229
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. 10.18632/oncotarget.1095427489349
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. 10.1073/pnas.101886610922308314
Najafi M., Farhood B., Mortezaee K.: “Cancer stem cells (CSCs) in cancer progression and therapy”. J. Cell. Physiol., 2019,234, 8381. 10.1002/jcp.2774030417375
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. 10.1007/s00204-015-1652-026659566
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. 17099695
Huang L., Ao Q., Zhang Q., Yang X., Xing H., Li F., et al.: “Hypoxia induced paclitaxel resistance in human ovarian cancers via hypoxia-inducible factor 1alpha”. J. Cancer Res. Clin. Oncol., 2010,136, 447. 10.1007/s00432-009-0675-419760195
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. 10.1007/s10456-018-9600-229383635
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. 10.1200/JCO.2009.27.444920479425
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. 10.1016/j.bbrc.2015.01.05325619133
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. 10.1038/
Manoochehri Khoshinani H., Afshar S., Najafi R.: “Hypoxia: A Double-Edged Sword inCancer Therapy”. Cancer Invest., 2016,34, 536. 10.1080/07357907.2016.124531727824512
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. 10.1002/cncr.2621521692061
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. 10.1093/jnci/95.7.51612671019
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. 30014256
Cook K.M., Figg W.D.: “Angiogenesis inhibitors: current strategies and future prospects”. CA Cancer J. Clin., 2010,60, 222. 20554717
Markowska A., Jaszczyńska-Nowinka K., Kaysiewicz J., Makówka A., Markowska J.: “Angiogenesis in gynecologic malignancies”. Curr. Gynecol. Oncol., 2015,13, 256. 10.15557/CGO
Januchowski R., Wojtowicz K., Zabel M.: “The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance”. Biomed. Pharmacother., 2013,67, 669. 10.1016/j.biopha.2013.04.0052372182377cba628-4d6f-450c-8610-b1434d3c7cb1
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. 10.1007/s00280-016-3213-527942929
Shah M.M., Landen C.N.: “Ovarian cancer stem cells: are they real and why are they important?” Gynecol. Oncol., 2014,132, 483. 10.1016/j.ygyno.2013.12.0012432139866bd8808-4bf0-41d4-ac51-13c9959a1af3
Tong W.W., Tong G.H., Liu Y.: “Cancer stem cells and hypoxia-inducible factors (Review).”. Int. J. Oncol., 2018,53, 469. 10.3892/ijo.2018.441729845228
Wang W., Zhao C., Jou D., 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. 2412299303dab476-4ba3-49d9-8718-9f0751c16acdWOS:000326204400017
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. 10.1371/journal.pone.016808828036332
Back to top