Background: Several human pathologies, including neoplasia and ischemic cardiovascular diseases, course with an unbalance between oxygen supply and demand (hypoxia). Cells within hypoxic regions respond with the induction of a specific genetic program, under the control of the Hypoxia Inducible Factor (HIF), that mediates their adaptation to the lack of oxygen. The activity of HIF is mainly regulated by the EGL-nine homolog (EGLN) enzymes that hydroxylate the alpha subunit of this transcription factor in an oxygen-dependent reaction. Hydroxylated HIF is then recognized and ubiquitinilated by the product of the tumor suppressor gene, pVHL, leading to its proteosomal degradation. Under hypoxia, the hydroxylation of HIF by the EGLNs is compromised due to the lack of oxygen, which is a reaction cosubstrate. Thus, HIF escapes degradation and drives the transcription of its target genes. Since the progression of the aforementioned pathologies might be influenced by activation of HIF-target genes, development of small molecules with the ability to interfere with the HIF-regulatory machinery is of great interest.
Abstract. Targeting the hypoxia response pathway and angiogenesis are two promising therapeutic strategies for cancer treatment. Their use as single strategies has important limitations. Thus, development of combined regimens has become an important step toward improving therapeutic efficacy. Also, non-invasive monitoring of the response to targeted biological therapies, as well as determination of the optimal schedule for combination regimens has become an active field of research over the last five years, with relevance for both preclinical and clinical settings. Here, we used an optical imaging method to non-invasively monitor the functional changes in HIF activity in response to antiangiogenic treatment in a xenograft model of human ovarian carcinoma. A bioluminescent reporter construct containing nine copies of the hypoxia response element upstream of the luciferase gene (9xHRE-luciferase) was characterized in vitro in a panel of tumor cell lines and in vivo in a subcutaneous xenograft model of ovarian carcinoma by means of optical imaging. We showed that in OVCAR-3 subcutaneous xenografts, the most abrupt change in the HIF functional reporter occurs before the onset of massive tumor growth. However, this system failed to detect hypoxia induced upon antiangiogenic treatment due to the compensating effects of increased hypoxia and decreased tumor cell viability caused by imbalanced neovascularization vs. tumor expansion. Therefore, the readout based on HIF functional reporter could be conditioned by the dynamics of tumor growth and angiogenesis, which is highly variable depending on the tumor type, tumor model and stage of progression. IntroductionOxygen availability is a fundamental restriction to the unlimited proliferative capacity characteristic of tumor cells. Thus, hypoxia is a common feature of most solid tumors. To surpass this barrier, tumor cells must evolve to acquire angiogenic potential, which endows them with the capacity to grow locally leading to tumor mass expansion. Therefore, suboptimal oxygen concentration (hypoxia) is one of the most relevant triggers of tumor angiogenesis and consequently the growth of tumors can be viewed as driven by cycles of hypoxia and angiogenesis. Taking these biological restrictions into account, halting angiogenesis has emerged as a general principle in which new antitumor therapies could be based.Over the last 30 years knowledge of the molecular and cellular basis of tumor angiogenesis has led to the development of a large number of antiangiogenic strategies, some of which are at present in clinical use (1,2). However, the biological output of antiangiogenic therapy has not been fully deciphered yet and may be variable depending on the tumor type, progression of the disease and antiangiogenic strategy. It is widely accepted that the dynamics of antiangiogenic drug response are initiated by an early phase of functional normalization of the tumor vasculature (early or normalization phase) characterized by an increased pericyte coverage and a decreased basal memb...
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