Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

Targeting HIF-1 for cancer therapy

Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.

Hypoxia — a key regulatory factor in tumour growth

Oxidative Stress, Inflammation, and Cancer: How Are They Linked?

Elevated rates of reactive oxygen species (ROS) have been detected in almost all cancers, where they promote many aspects of tumour development and progression. However, tumour cells also express increased levels of antioxidant proteins to detoxify from ROS, suggesting that a delicate balance of intracellular ROS levels is required for cancer cell function. Further, the radical generated, the location of its generation, as well as the local concentration is important for the cellular functions of ROS in cancer. A challenge for novel therapeutic strategies will be the fine tuning of intracellular ROS signalling to effectively deprive cells from ROS-induced tumour promoting events, towards tipping the balance to ROS-induced apoptotic signalling. Alternatively, therapeutic antioxidants may prevent early events in tumour development, where ROS are important. However, to effectively target cancer cells specific ROS-sensing signalling pathways that mediate the diverse stress-regulated cellular functions need to be identified. This review discusses the generation of ROS within tumour cells, their detoxification, their cellular effects, as well as the major signalling cascades they utilize, but also provides an outlook on their modulation in therapeutics.

/pdf/reactive-oxygen-species-in-cancer-2cc2eau8py.pdf

Reactive oxygen species in cancer

Hypoxia is a feature of most tumours, albeit with variable incidence and severity within a given patient population. It is a negative prognostic and predictive factor owing to its multiple contributions to chemoresistance, radioresistance, angiogenesis, vasculogenesis, invasiveness, metastasis, resistance to cell death, altered metabolism and genomic instability. Given its central role in tumour progression and resistance to therapy, tumour hypoxia might well be considered the best validated target that has yet to be exploited in oncology. However, despite an explosion of information on hypoxia, there are still major questions to be addressed if the long-standing goal of exploiting tumour hypoxia is to be realized. Here, we review the two main approaches, namely bioreductive prodrugs and inhibitors of molecular targets upon which hypoxic cell survival depends. We address the particular challenges and opportunities these overlapping strategies present, and discuss the central importance of emerging diagnostic tools for patient stratification in targeting hypoxia.

Targeting hypoxia in cancer therapy

Tissue hypoxia results from an inadequate supply of oxygen (O(2)) that compromises biologic functions. Evidence from experimental and clinical studies increasingly points to a fundamental role for hypoxia in solid tumors. Hypoxia in tumors is primarily a pathophysiologic consequence of structurally and functionally disturbed microcirculation and the deterioration of diffusion conditions. Tumor hypoxia appears to be strongly associated with tumor propagation, malignant progression, and resistance to therapy, and it has thus become a central issue in tumor physiology and cancer treatment. Biochemists and clinicians (as well as physiologists) define hypoxia differently; biochemists define it as O(2)-limited electron transport, and physiologists and clinicians define it as a state of reduced O(2) availability or decreased O(2) partial pressure that restricts or even abolishes functions of organs, tissues, or cells. Because malignant tumors no longer execute functions necessary for homeostasis (such as the production of adequate amounts of adenosine triphosphate), the physiology-based definitions of the term "hypoxia" are not necessarily valid for malignant tumors. Instead, alternative definitions based on clinical, biologic, and molecular effects that are observed at O(2) partial pressures below a critical level have to be applied.

/pdf/tumor-hypoxia-definitions-and-current-clinical-biologic-and-5gkgj1718s.pdf

Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects.

Data from 125 studies describing the pretreatment oxygenation status as measured in the clinical setting using the computerized Eppendorf pO2 histography system have been compiled in this article. Tumor oxygenation is heterogeneous and severely compromised as compared to normal tissue. Hypoxia results from inadequate perfusion and diffusion within tumors and from a reduced O2 transport capacity in anemic patients. The development of tumor hypoxia is independent of a series of relevant tumor characteristics (e.g., clinical size, stage, histology, and grade) and various patient demographics. Overall median pO2 in cancers of the uterine cervix, head and neck, and breast is 10 mm Hg with the overall hypoxic fraction (pO2 <or= 2.5 mm Hg) being approx. 25%. Metastatic lesions do not substantially deviate from the oxygenation status of (their) primary tumors. Whereas normal tissue oxygenation is independent of the hemoglobin level over the range of 8-15 g/dL, hypoxia is more pronounced in anemic patients and above this range in some cancers. Identification of tumor hypoxia may allow an assessment of a tumor's potential to develop an aggressive phenotype or acquired treatment resistance, both of which lead to poor prognosis. Detection of hypoxia in the clinical setting may therefore be helpful in selecting high-risk patients for individual and/or more intensive treatment schedules.

Detection and characterization of tumor hypoxia using pO2 histography.

Publisher Summary This chapter discusses tumor hypoxia and malignant progression. Hypoxic (or anoxic) areas arise as a result of an imbalance between the supply and the consumption of oxygen. Whereas in normal tissues or organs the O2 supply matches the metabolic requirements, in locally advanced solid tumors the O2 consumption rate of neoplastic as well as stromal cells may outweigh an insufficient oxygen supply and result in the development of tissue areas with very low O2 levels. Major pathogenetic mechanisms involved in the emergence of hypoxia in solid tumors are (a) severe structural and functional abnormalities of the tumor microvessels (b) a deterioration of the diffusion geometry, and (c) tumor-associated and/or therapy-induced anemia leading to a reduced O2 transport capacity of the blood. This chapter discusses current information from experimental and clinical studies, which illustrates the interaction between tissue hypoxia and the phenomenon of malignant progression. Evidence, characterization and pathogenesis of tumor hypoxia, and the role of hypoxia in malignant progressionare discussed.

Tumor hypoxia and malignant progression.

There is evidence from experimental work that hypoxia induces apoptosis in apoptosis-sensitive neoplastic cells and that this apoptotic sensitivity is lost during malignant progression. Oxygenation profiles and apoptotic indices in human squamous cell cancer of the uterine cervix have been determined, and a subgroup of tumors has been identified with low apoptotic index despite pronounced hypoxia representing carcinomas that consist of neoplastic cells with diminished apoptotic potential. These hypoxic low-apoptotic tumors show a high probability for lymphatic spread and for recurrence despite adjuvant treatment with radiation or chemotherapy in addition to radical surgery. The clinical results presented strongly support the hypothesis derived from experimental studies that the selection of apoptosis-insensitive neoplastic cell phenotypes in a hypoxic microenvironment is an important mechanism for malignant progression in solid tumors.

https://cancerres.aacrjournals.org/content/canres/59/18/4525.full.pdf

Michael Höckel

Papers

Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects.

Detection and characterization of tumor hypoxia using pO2 histography.

Tumor hypoxia and malignant progression.

Hypoxic cervical cancers with low apoptotic index are highly aggressive.

Hypoxia and Radiation Response in Human Tumors.