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.
"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. "
[Show abstract][Hide abstract] ABSTRACT: Cells maintain intracellular pH (pHi) within a narrow range (7.1-7.2) by controlling membrane proton pumps and transporters whose activity is set by intra-cytoplasmic pH sensors. These sensors have the ability to recognize and induce cellular responses to maintain the pHi, often at the expense of acidifying the extracellular pH. In turn, extracellular acidification impacts cells via specific acid-sensing ion channels (ASICs) and proton-sensing G-protein coupled receptors (GPCRs). In this review, we will discuss some of the major players in proton sensing at the plasma membrane and their downstream consequences in cancer cells and how these pH-mediated changes affect processes such as migration and metastasis. The complex mechanisms by which they transduce acid pH signals to the cytoplasm and nucleus are not well understood. However, there is evidence that expression of proton-sensing GPCRs such as GPR4, TDAG8, and OGR1 can regulate aspects of tumorigenesis and invasion, including cofilin and talin regulated actin (de-)polymerization. Major mechanisms for maintenance of pHi homeostasis include monocarboxylate, bicarbonate, and proton transporters. Notably, there is little evidence suggesting a link between their activities and those of the extracellular H(+)-sensors, suggesting a mechanistic disconnect between intra- and extracellular pH. Understanding the mechanisms of pH sensing and regulation may lead to novel and informed therapeutic strategies that can target acidosis, a common physical hallmark of solid tumors.
Frontiers in Physiology 12/2013; 4:370. DOI:10.3389/fphys.2013.00370 · 3.53 Impact Factor
"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). "
[Show abstract][Hide abstract] ABSTRACT: The diagnosis of neoplastic disease still lays its foundations on the detection of altered tissue morphology. Most importantly, cancer begins, at least in many cases as a disease with altered tissue pattern formation. It is therefore rather surprising that the issue regarding the possible mechanistic role of such property in the pathogenesis of cancer has received relatively little attention so far. To be more specific, we need to ask the following question: is altered tissue pattern formation a mere bystander, with its pervasive presence along the entire carcinogenic sequence, or does it play a role in fuelling this process? Pathways related to morphogenesis and to the establishment of cell polarity will be considered for their possible mechanistic involvement in early phases of neoplastic disease. Evidences and hypotheses relating altered tissue pattern formation to the emergence of the tumor microenvironment and to neoplastic progression will be discussed.
Progress in Histochemistry and Cytochemistry 09/2012; 47(3):175-207. DOI:10.1016/j.proghi.2012.08.001 · 3.64 Impact Factor
"Specifically, this population produces an acidic environment through upregulated glycolysis that is toxic to competing populations but not to its own cells. Clinical observations in both breast  and cervical cancers  have found evidence that successful adaptation to the hypoxia-glycolysis-acidosis sequence in the microenvironment is crucial during carcinogenesis. "
[Show abstract][Hide abstract] ABSTRACT: The transition from premalignant to invasive tumour growth is a prolonged multistep process governed by phenotypic adaptation to changing microenvironmental selection pressures. Cancer prevention strategies are required to interrupt or delay somatic evolution of the malignant invasive phenotype. Empirical studies have consistently demonstrated that increased physical activity is highly effective in reducing the risk of breast cancer but the mechanism is unknown.
Here we propose the hypothesis that exercise-induced transient systemic acidosis will alter the in situ tumour microenvironment and delay tumour adaptation to regional hypoxia and acidosis in the later stages of carcinogenesis. We test this hypothesis using a hybrid cellular automaton approach. This model has been previously applied to somatic evolution on epithelial surfaces and demonstrated three phases of somatic evolution, with cancer cells escaping in turn from the constraints of limited space, nutrient supply and waste removal. In this paper we extend the model to test our hypothesis that transient systemic acidosis is sufficient to arrest, or at least delay, transition from in situ to invasive cancer.
Model simulations demonstrate that repeated episodes of transient systemic acidosis will interrupt critical evolutionary steps in the later stages of carcinogenesis resulting in substantial delay in the evolution to the invasive phenotype. Our results suggest transient systemic acidosis may mediate the observed reduction in cancer risk associated with increased physical activity.
Biology Direct 04/2010; 5(1):22. DOI:10.1186/1745-6150-5-22 · 4.66 Impact Factor
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