The text consists of two sections, one for those studying or practicing diagnostic radiology, nuclear medicine and radiation oncology; the other for those engaged in the study or clinical practice of radiation oncology--a new chapter, on radiologic terrorism, is specifically for those in the radiation sciences who would manage exposed individuals in the event of a terrorist event. The 17 chapters in Section I represent a general introduction to radiation biology and a complete, self-contained course especially for residents in diagnostic radiology and nuclear medicine that follows the Syllabus in Radiation Biology of the RSNA. The 11 chapters in Section II address more in-depth topics in radiation oncology, such as cancer biology, retreatment after radiotherapy, chemotherapeutic agents and hyperthermia.

Radiobiology for the Radiologist

In this review, the importance of the hypoxia inducible factor (HIF) pathway in tumorigenesis and cancer treatment outcomes will be discussed. The outcomes of phase II and III clinical trials of direct HIF inhibitors in the treatment of cancer will be reviewed. The HIF signaling pathway is activated by tumor-induced hypoxia or by inactivating mutations of the VHL gene. HIF is a transcription factor which regulates the expression of genes involved in adjusting mechanisms to hypoxia such as angiogenesis or apoptosis as well as tumor growth, invasion, and metastasis. The HIF pathway has a key role in development of resistance to different treatment modalities and higher expression of the HIF molecule is associated with poor prognosis. Clinical studies of the HIF inhibitors in patients with advanced/refractory cancers suggest benefit and warrant further studies of the HIF inhibitors either as a single agent or in combination with other therapeutic agents.

HIF Inhibitors: Status of Current Clinical Development

Hypoxia is a common feature of many solid tumors, including hepatocellular carcinoma (HCC) Hypoxia can promote tumor progression and induce radiation and chemotherapy resistance As one of the major mediators of hypoxic response, hypoxia inducible factor-1 (HIF-1) has been shown to activate hypoxia-responsive genes, which are involved in multiple aspects of tumorigenesis and cancer progression, including proliferation, metabolism, angiogenesis, invasion, metastasis and therapy resistance It has been demonstrated that a high level of HIF-1 in the HCC microenvironment leads to enhanced proliferation and survival of HCC cells Accordingly, overexpression, of HIF-1 is associated with poor prognosis in HCC In this review, we described the mechanism by which HIF-1 is regulated and how HIF-1 mediates the biological effects of hypoxia in tissues We also summarized the latest findings concerning the role of HIF-1 in the development of HCC, which could shed light on new therapeutic approaches for the treatment of HCC

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The Role of Hypoxia Inducible Factor-1 in Hepatocellular Carcinoma

Liver disease is a growing global health problem, as deaths from end-stage liver cirrhosis and cancer are rising across the world. At present, pharmacologic approaches to effectively treat or prevent liver disease are extremely limited. Hypoxia-inducible factor (HIF) is a transcription factor that regulates diverse signaling pathways enabling adaptive cellular responses to perturbations of the tissue microenvironment. HIF activation through hypoxia-dependent and hypoxia-independent signals have been reported in liver disease of diverse etiologies, from ischemia-reperfusion-induced acute liver injury to chronic liver diseases caused by viral infection, excessive alcohol consumption, or metabolic disorders. This review summarizes the evidence for HIF stabilization in liver disease, discusses the mechanistic involvement of HIFs in disease development, and explores the potential of pharmacological HIF modifiers in the treatment of liver disease.

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Hypoxia-inducible factors as molecular targets for liver diseases

Understanding the role of cytokines in Glioblastoma Multiforme pathogenesis.

Purpose: Hypoxia-inducible factor 1 (HIF-1) promotes cancer cell survival and tumor progression. The specific role played by HIF-1 and tumor–stromal interactions toward determining tumor resistance to radiation treatment remains undefined. We applied a multimodality preclinical imaging platform to mechanistically characterize tumor response to radiation, with a focus on HIF-1–dependent resistance pathways. Methods: C6 glioma and HN5 human squamous carcinoma cells were stably transfected with a dual HIF-1 signaling reporter construct (dxHRE-tk/eGFP-cmvRed2XPRT). Reporter cells were serially interrogated in vitro before and after irradiation as monolayer and multicellular spheroid cultures and as subcutaneous xenografts in nu/nu mice. Results: In vitro , single-dose irradiation of C6 and HN5 reporter cells modestly impacted HIF-1 signaling in normoxic monolayers and inhibited HIF-1 signaling in maturing spheroids. In contrast, irradiation of C6 or HN5 reporter xenografts with 8 Gy in vivo elicited marked upregulation of HIF-1 signaling and downstream proangiogenic signaling at 48 hours which preceded recovery of tumor growth. In situ ultrasound imaging and dynamic contrast-enhanced (DCE) MRI indicated that HIF-1 signaling followed acute disruption of stromal vascular function. High-resolution positron emission tomography and dual-contrast DCE-MRI of immobilized dorsal skin window tumors confirmed postradiotherapy HIF-1 signaling to spatiotemporally coincide with impaired stromal vascular function. Targeted disruption of HIF-1 signaling established this pathway to be a determinant of tumor radioresistance. Conclusions: Our results illustrate that tumor radioresistance is mediated by a capacity to compensate for stromal vascular disruption through HIF-1–dependent proangiogenic signaling and that clinically relevant vascular imaging techniques can spatially define mechanisms associated with tumor irradiation. Mol Cancer Res; 9(3); 259–70. ©2011 AACR .

https://mcr.aacrjournals.org/content/molcanres/9/3/259.full.pdf

Arun Kumar Thitai

Papers

HIF-1–Dependent Stromal Adaptation to Ischemia Mediates In Vivo Tumor Radiation Resistance