Hypoxia or low oxygen concentration in tumor microenvironment has widespread effects ranging from altered angiogenesis and lymphangiogenesis, tumor metabolism, growth, and therapeutic resistance in different cancer types. A large number of these effects are mediated by the transcription factor hypoxia inducible factor 1⍺ (HIF-1⍺) which is activated by hypoxia. HIF1⍺ induces glycolytic genes and reduces mitochondrial respiration rate in hypoxic tumoral regions through modulation of various cells in tumor microenvironment like cancer-associated fibroblasts. Immune evasion driven by HIF-1⍺ further contributes to enhanced survival of cancer cells. By altering drug target expression, metabolic regulation, and oxygen consumption, hypoxia leads to enhanced growth and survival of cancer cells. Tumor cells in hypoxic conditions thus attain aggressive phenotypes and become resistant to chemo- and radio- therapies resulting in higher mortality. While a number of new therapeutic strategies have succeeded in targeting hypoxia, a significant improvement of these needs a more detailed understanding of the various effects and molecular mechanisms regulated by hypoxia and its effects on modulation of the tumor vasculature. This review focuses on the chief hypoxia-driven molecular mechanisms and their impact on therapeutic resistance in tumors that drive an aggressive phenotype.

Impact statement

Hypoxia contributes to tumor aggressiveness and promotes growth of many solid tumors that are often resistant to conventional therapies. In order to achieve successful therapeutic strategies targeting different cancer types, it is necessary to understand the molecular mechanisms and signaling pathways that are induced by hypoxia. Aberrant tumor vasculature and alterations in cellular metabolism and drug resistance due to hypoxia further confound this problem. This review focuses on the implications of hypoxia in an inflammatory TME and its impact on the signaling and metabolic pathways regulating growth and progression of cancer, along with changes in lymphangiogenic and angiogenic mechanisms. Finally, the overarching role of hypoxia in mediating therapeutic resistance in cancers is discussed.

中文翻译：

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缺氧肿瘤微环境：对癌症治疗的意义。

肿瘤微环境中的低氧或低氧浓度具有广泛的影响，范围从改变的血管生成和淋巴管生成，肿瘤代谢，生长以及不同类型癌症的治疗抗性。大量的这些作用是由缺氧激活的转录因子缺氧诱导因子1⍺（HIF-1⍺）介导的。HIF1β通过调节肿瘤微环境中各种细胞（如癌症相关的成纤维细胞），诱导缺糖性肿瘤区域的糖酵解基因并降低线粒体呼吸速率。HIF-1⍺驱动的免疫逃逸进一步有助于提高癌细胞的存活率。通过改变药物靶标的表达，代谢调节和耗氧量，缺氧导致癌细胞的生长和存活增强。因此，低氧条件下的肿瘤细胞会获得侵袭性表型，并对化学疗法和放射疗法产生抵抗力，从而导致更高的死亡率。尽管许多新的治疗策略已成功地针对缺氧，但是这些的显着改善需要对缺氧调节的各种作用和分子机制及其对肿瘤脉管系统调节的作用进行更详细的了解。这篇综述集中在主要的缺氧驱动的分子机制及其对驱动侵袭性表型的肿瘤的治疗抗性的影响。这些的显着改善需要对缺氧调节的各种作用和分子机制及其对肿瘤脉管系统调节的作用有更详细的了解。这篇综述集中在主要的缺氧驱动的分子机制及其对驱动侵袭性表型的肿瘤的治疗抗性的影响。这些的显着改善需要对缺氧调节的各种作用和分子机制及其对肿瘤脉管系统调节的作用有更详细的了解。这篇综述集中在主要的缺氧驱动的分子机制及其对驱动侵袭性表型的肿瘤的治疗抗性的影响。

影响陈述

缺氧有助于肿瘤侵袭性并促进许多通常对常规疗法有抵抗力的实体瘤的生长。为了实现针对不同癌症类型的成功治疗策略，有必要了解缺氧诱导的分子机制和信号传导途径。缺氧引起的异常肿瘤脉管系统以及细胞代谢和耐药性的改变进一步混淆了这个问题。这篇综述的重点是缺氧在炎性TME中的意义及其对调节癌症生长和进展的信号传导和代谢途径的影响，以及淋巴管生成和血管生成机制的变化。最后，讨论了缺氧在介导癌症的治疗抵抗中的主要作用。