乏氧诱导因子-1与肿瘤乏氧的研究进展

乏氧是实体肿瘤发展过程中的普遍现象,它能诱导肿瘤细胞发生一系列基因表达的改变以适应环境.乏氧诱导因子-1(hypoxia inducible factor-1,HIF-1)是其调控核心.一方面,HIF-1通过与靶基因启动子序列中的HRE结合调控其表达,增加肿瘤新血管和红细胞生成、改变能量代谢途径等,以增加氧的利用率、减少氧的消耗,同时通过调控细胞周期调节蛋白、凋亡相关基因的表达改变细胞周期、抑制细胞凋亡;另一方面,HIF-1的表达受多种基因产物的调控,如VHL,PTEN等.HIF-1有多种生物学功能,如促进红细胞生成、肿瘤血管形成、促进肿瘤的转移和侵袭等.通过药物或基因治疗的方式抑制HIF-1的活性是治疗肿瘤的一种新途径.     

缺氧诱导因子-1与肿瘤

缺氧诱导因子－1（hypoxia inducible factor-1,HIF-1)是调控细胞氧平衡和诱导缺氧反应基因表达的重要的DNA结合蛋白，与肿瘤的发生、发展密切相关。HIF－1受多种抑癌基因、癌基因、生长因子的调节，参与对肿瘤生理过程的调控。了解HIF－1的作用机制，人工调控肿瘤细胞内的HIF－1水平有助于对肿瘤的治疗。     

肿瘤乏氧检测方法研究进展

肿瘤的氧合状态是放疗、化疗、生物治疗、加热等治疗的重要的影响因素,肿瘤乏氧细胞对放射治疗的敏感性低,对化疗、生物治疗等同样较为耐受。肿瘤乏氧同样是局部复发和远处转移的重要危险因素。如果能够准确地测定个体肿瘤的氧合状态,以此指导治疗方案的选择将有助于提高肿瘤的疗效。目前虽然乏氧检测的技术还未完全成熟,但已有多种检测方法应用于临床,其前景无疑是广阔的。     

不同剂量川芎对PG干细胞样细胞低氧微环境改善的研究

[目的]观察体内实验中不同剂量川芎对肿瘤干细胞样细胞低氧微环境的影响.[方法]通过无血清培养获得的干细胞样细胞并鉴定,将已鉴定的球细胞接种于裸鼠腋下,将裸鼠平均随机分为3组,即对照组、高剂量川芎组、低剂量川芎组,21d后检测抑瘤率,Western blot检测瘤体ABCG2、HIF-1α蛋白表达,RT-PCR检测HIF-1α mRNA表达.[结果]低剂量川芎对PG-BE1干细胞样细胞具有杀伤作用,可在蛋白水平上抑制ABCG2的表达(P＜0.05).低剂量川芎同时还可在蛋白及mRNA的水平上抑制HIF-1α的表达.[结论]低剂量川芎对肿瘤干细胞的杀伤作用可能与其抑制HIF-1α蛋白表达,改善肿瘤乏氧微环境有关.     

基于纳米生物材料的肿瘤乏氧调控与放疗增效研究进展

放射治疗是临床肿瘤治疗常用的一种治疗策略,包括将放射性核素注射或植入体内的核素内放疗以及利用外界的射线(如X射线)对肿瘤部位进行照射的外照射放疗两大类.由于氧分子在电离辐射杀伤肿瘤细胞的过程中发挥着重要的作用,而实体肿瘤内部却普遍存在乏氧的微环境,肿瘤乏氧是导致其对放疗耐受的重要原因之一.近年来,随着生物材料和纳米技术...     

Energy Status Parameters, Hypoxia Fraction and Radiocurability Across Tumor Types

Under full nutrient in vitro conditions, the cellular adenylate energy charge of six different rodent and human tumor cell types was identical, i.e., 0.94 ± 0.01, suggesting the potential utility of this parameter as a cell (and tissue) independent marker of nutrient deprivation and hypoxia, across tumor types. The adenylate energy charge values of tumors, arising from these cells, was reduced and variable ranging from 0.72 to 0.91 for the various tumor types. However, neither the tumor adenylate energy charge, NTP/Pi, nor PCr/Pi ratios correlated with the radiobiologic hypoxic cell fractions across tumor types. The reduced adenylate energy charge in vivo suggests varying degrees of nutrient deprivation in the different tumor types, however, factors other than or in addition to hypoxia likely contribute to tumor energy status.     

Tumor Hypoxia and Gene Expression: Implications for Malignant Progression and Therapy

Most histopathological classifications of human cancers include significant numbers of hypoxic cells. There is increasing evidence that, at least in certain types of human solid tumors, there is a positive relationship between the presence of hypoxia and poor outcome after radiation therapy alone or radiation combined with other therapies. Hypoxia appears to be an independent prognostic factor. There is evidence for enhanced malignant progression associated with hypoxia, including locoregional invasion and distant metastases. The presence of hypoxia may negatively affect outcome by induction of radiation resistance by the classical oxygen effect and/or by effects on gene expression and malignant progression, causing more aggressive locoregional and distant disease. It is now clear that hypoxia has the potential to influence expression of genes and activities of associated proteins that regulate growth and tissue homeostasis, resulting in cellular phenotypic heterogeneity. The molecular pathways involved in signaling and regulating changes in gene activities in response to external stresses such as hypoxia are becoming known. Identification of patients with hypoxic tumors will lead to improved selective therapy.     

Tumor Hypoxia As an Enhancer of Inflammation-Mediated Metastasis: Emerging Therapeutic Strategies

Metastasis is the leading cause of cancer-related deaths. Recent research has implicated tumor inflammation as a promoter of metastasis. Myeloid, lymphoid, and mesenchymal cells in the tumor microenvironment promote inflammatory signaling amongst each other and together with cancer cells to modulate sustained inflammation, which may enhance cancer invasiveness. Tumor hypoxia, a state of reduced available oxygen present in the majority of solid tumors, acts as a prognostic factor for a worse outcome and is known to have a role in tumor inflammation through the regulation of inflammatory mediator signals in both cancer and neighboring cells in the microenvironment. Multiple methods to target tumor hypoxia have been developed and tested in clinical trials, and still more are emerging as the impacts of hypoxia become better understood. These strategies include mechanistic inhibition of the hypoxia inducible factor signaling pathway and hypoxia activated pro-drugs, leading to both anti-tumor and anti-inflammatory effects. This prompts a need for further research on the prevention of hypoxia-mediated inflammation in cancer. Hypoxia-targeting strategies seem to have the most potential for therapeutic benefit when combined with traditional chemotherapy agents. This paper will serve to summarize the role of the inflammatory response in metastasis, to discuss how hypoxia can enable or enhance inflammatory signaling, and to review established and emerging strategies to target the hypoxia-inflammation-metastasis axis.     

Localized Hypoxia Results in Spatially Heterogeneous Metabolic Signatures in Breast Tumor Models

Tumor hypoxia triggers signaling cascades that significantly affect biologic outcomes such as resistance to radiotherapy and chemotherapy in breast cancer. Hypoxic regions in solid tumor are spatially heterogeneous. Therefore, delineating the origin and extent of hypoxia in tumors is critical. In this study, we have investigated the effect of hypoxia on different metabolic pathways, such as lipid and choline metabolism, in a human breast cancer model. Human MDA-MB-231 breast cancer cells and tumors, which were genetically engineered to express red fluorescent tdTomato protein under hypoxic conditions, were used to investigate hypoxia. Our data were obtained with a novel three-dimensional multimodal molecular imaging platform that combines magnetic resonance (MR) imaging, MR spectroscopic imaging (MRSI), and optical imaging of hypoxia and necrosis. A higher concentration of noninvasively detected total choline-containing metabolites (tCho) and lipid CH3 localized in the tdTomato-fluorescing hypoxic regions indicated that hypoxia can upregulate tCho and lipid CH3 levels in this breast tumor model. The increase in tCho under hypoxia was primarily due to elevated phosphocholine levels as shown by in vitro MR spectroscopy. Elevated lipid CH3 levels detected under hypoxia were caused by an increase in mobile MR-detectable lipid droplets, as demonstrated by Nile Red staining. Our findings demonstrate that noninvasive MRSI can help delineate hypoxic regions in solid tumors by means of detecting the metabolic outcome of tumor hypoxia, which is characterized by elevated tCho and lipid CH3.     

Alveolar Hypoxia Promotes Murine Lung Tumor Growth through a VEGFR-2/EGFR-Dependent Mechanism

Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia. Mice exposed to chronic hypoxia developed tumors with increased volume compared with normoxic controls. Both lungs and tumors from hypoxic mice showed a preferential stabilization of HIF-2α and increased expression of VEGF-A, FGF2, and their receptors as well as other survival, proliferation, and angiogenic signaling pathways regulated by HIF-2α. We showed that tumors arising in hypoxic animals have increased sensitivity to VEGFR-2/EGFR inhibition, as chemoprevention with vandetanib showed markedly increased activity in hypoxic mice. These studies showed that lung tumors arising in a hypoxic microenvironment express increased growth, angiogenic, and survival signaling that could contribute to the increased lung cancer risk in COPD. Furthermore, the differential sensitivity of tumors arising in hypoxia to VEGFR-2/EGFR inhibition suggests that the altered signaling present in tumors arising in hypoxic lung might be therapeutically exploited in patients with underlying COPD. Cancer Prev Res; 5(8); 1061-71. ?2012 AACR.     

Noninvasive Multimodality Imaging of the Tumor Microenvironment: Registered Dynamic Magnetic Resonance Imaging and Positron Emission Tomography Studies of a Preclinical Tumor Model of Tumor Hypoxia

In vivo knowledge of the spatial distribution of viable, necrotic, and hypoxic areas can provide prognostic information about the risk of developing metastases and regional radiation sensitivity and may be used potentially for localized dose escalation in radiation treatment. In this study, multimodality in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging using stereotactic fiduciary markers in the Dunning R3327-AT prostate tumor were performed, focusing on the relationship between dynamic contrast-enhanced (DCE) MRI using Magnevist (Gd-DTPA) and dynamic ¹⁸F-fluoromisonidazole (¹⁸F-Fmiso) PET. The noninvasive measurements were verified using tumor tissue sections stained for hematoxylin/eosin and pimonidazole. To further validate the relationship between ¹⁸F-Fmiso and pimonidazole uptake, ¹⁸F digital autoradiography was performed on a selected tumor and compared with the corresponding pimonidazole-stained slices. The comparison of Akep values (kep = rate constant of movement of Gd-DTPA between the interstitial space and plasma and A = amplitude in the two-compartment model (Hoffmann U, Brix G, Knopp MV, Hess T and Lorenz WJ (1995). Magn Reson Med 33, 506–514) derived from DCE-MRI studies and from early ¹⁸F-Fmiso uptake PET studies showed that tumor vasculature is a major determinant of early ¹⁸F-Fmiso uptake. A negative correlation between the spatial map of Akep and the slope map of late (last 1 hour of the dynamic PET scan) ¹⁸F-Fmiso uptake was observed. The relationships between DCE-MRI and hematoxylin/eosin slices and between ¹⁸F-Fmiso PET and pimonidazole slices confirm the validity of MRI/PET measurements to image the tumor microenvironment and to identify regions of tumor necrosis, hypoxia, and well-perfused tissue.     

Metastasis in Melanoma Xenografts Is Associated with Tumor Microvascular Density Rather than Extent of Hypoxia

The development of metastases has been shown to be associated with the microvascular density of the primary tumor in some clinical studies and with the extent of hypoxia in others. The aim of this study was to investigate the validity of these apparently inconsistent observations and to reveal possible links between them. Xenografted tumors of nine melanoma cell lines established from patients with diseases differing in aggressiveness were studied. The aggressiveness of the cell lines was assessed by measuring their lung colonization potential, invasiveness, angiogenic potential, and tumorigenicity. Spontaneous metastasis was assessed in untreated mice and mice treated with neutralizing antibody against vascular endothelial growth factor A (VEGF-A) or interleukin 8 (IL-8). Microvascular density was scored in histologic preparations. Hypoxic fractions were measured by using a radiobiologic assay and a pimonidazole-based immunohistochemical assay. The aggressiveness of the melanoma lines reflected the aggressiveness of the donor patients'' tumors. The metastatic propensity was associated with the microvascular density but not with the hypoxic fraction. Anti-VEGF-A and anti-IL-8 treatments resulted in decreased microvascular density and reduced incidence of metastases in all lines. Large hypoxic fractions were not a secondary effect of high cellular aggressiveness, whereas the microvascular density was associated with the cellular aggressiveness. The metastatic propensity was governed by the angiogenic potential of the tumor cells. The differences in microvascular density among the lines were most likely a consequence of differences in the constitutive angiogenic potential rather than differences in hypoxia-induced angiogenesis. VEGF-A and IL-8 may be important therapeutic targets for melanoma.