Lee WY, Huang SC, Hsu KF, Tzeng CC, Shen WLRoles for hypoxia-regulated genes during cervical carcinogenesis: somatic evolution during the hypoxia-glycolysis-acidosis sequence. Gynecol Oncol 108: 377-384

Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan.
Gynecologic Oncology (Impact Factor: 3.77). 03/2008; 108(2):377-84. DOI: 10.1016/j.ygyno.2007.10.034
Source: PubMed


Malignant phenotypic traits are caused by microenvironmental selection pressures during carcinogenesis. Hypoxia can drive a tumor toward a more aggressive malignant phenotype. The objective was to better understand the role of the hypoxia-regulated genes in cervical carcinogenesis.
We analyzed the expression of the hypoxia-regulated genes, including hypoxia-inducible factor-1alpha (HIF-1alpha), erythropoietin (Epo), vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT1), carbonic anhydrase IX (CAIX), and MET, in cervical cell lines and human tissue samples of cervical intraepithelial neoplasia (CIN I-III) and invasive squamous cell carcinoma (ISCC).
CAIX and MET were expressed in cervical carcinoma cell lines, but not in normal or human papillomavirus-immortalized cervical cells. In clinical tissue samples, Epo, VEGF, GLUT1, and CAIX were not detected in normal squamous epithelia. GLUT1 was expressed in nearly all cases of CIN and ISCC, however, CAIX was expressed only in CIN III and ISCC. HIF-1alpha and MET expression was confined to the basal cells in normal squamous epithelia and was detected in the dysplastic cells of CIN and ISCC.
The role of HIF-1alpha and MET changes from response to proliferation to tumor progression during cervical carcinogenesis. GLUT1 expression, a glycolytic phenotype adaptive to glycolysis, occurs early during cervical carcinogenesis and is a specific marker for dysplasia or carcinoma. MET and CAIX may contribute tumor progression in later stage. CAIX expression, an acid-resistant phenotype, may be a powerful adaptive advantage during carcinogenesis. Successful adaptation to the hypoxia-glycolysis-acidosis sequence in a microenvironment is crucial during carcinogenesis.

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    • "The MCT family is composed of 14 members with similar topology and can be found expressed in a wide range of tissues. Only 4 isoforms (MCT1–MCT4) have been functionally characterized as proton-linked monocarboxylate transporters (Morris and Felmlee, 2008; Halestrap, 2012; Halestrap and Wilson, 2012). This is critical as MCTs (MCT1 and MCT4) are routinely overexpressed in tumors primarily regulating the efflux of lactate and protons as byproducts of glycolysis from intracellular to extracellular space in order to maintain physiological pH i thus, contributing to extracellular acidosis. "
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    • "Furthermore, elegant mathematical modelling supports the conclusion that harsh selective microenvironments , such as that imposed by hypoxia, are associated with a type of cell growth with fingering margins, dominated by a few clones with aggressive traits, as it is seen in invasive cancers (Quaranta et al., 2008). Pertinent to this point, the extracellular acidic microenvironment mentioned above and contributed by the hypoxia-induced metabolic alterations can also fuel invasion and metastasis through its toxic effect on surrounding tissue (Silva et al., 2009; Lou et al., 2011) Although the hypoxia-induced alterations in the tumor microenvironment described in the preceding paragraphs are typically associated to late phases of neoplastic progression, data documenting the activation of the HIF pathway in human preneoplasia have been reported (Lee et al., 2008; Chen et al., 2010). A recent study, performed on clinical samples of breast tissue, found increased expression of HIF-1 in ductal hyperplasia, atypical ductal hyperplasia and ductal carcinoma in situ, and the latter lesions also expressed both GLUT1 and CA-IX (Chen et al., 2010). "
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