Roles of oxygen in the tumorigenesis, progression, and treatment of breast cancer

Darie, Costel C.1,*; Hukovic, Angiolina1; Maynard, Veronica D.1; Neagu, Anca-Narcisa2,*

Author Information

1Biochemistry & Proteomics Laboratories, Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, NY, USA

2Laboratory of Animal Histology, Faculty of Biology, “Alexandru Ioan Cuza” University of Ia.i, Iasi, Romania

*Correspondence to: Costel C. Darie, PhD, cdarie@clarkson.edu; Anca-Narcisa Neagu, PhD, aneagu@uaic.ro.

Funding:This work was supported in part by the National Cancer Institute of the National Institutes of Health under Award Number R15CA260126 (to CCD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Abstract

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death among women worldwide. Poor prognosis in breast cancer patients is often linked to the presence of intratumoral hypoxic areas caused by abnormal vascularization and insufficient oxygen availability, which results in energetic crisis in cancer cells; metabolic and epigenetic reprogramming; the transcription of genes involved in angiogenesis; cancer cell proliferation; increased motility, aggressiveness and metastasis; the accumulation of mutations; genomic instability; the maintenance of stem cell characteristics; stromal cell recruitment; extracellular matrix remodeling; chronic inflammation; immune evasion; and adaptive responses in the tumoral microbiota. Furthermore, hypoxia is often correlated with resistance to traditional antitumor treatments used alone or in combination, which results in the need to implement novel therapies to overcome or alleviate the negative effects of oxygen deprivation in breast cancer theranostics. In breast cancer modeling research, micro- and nanofabrication-based technologies, including breast cancer-on-chip and breast cancer metastasis-on-chip platforms, are able to recapitulate the metastatic cascade of breast cancer in different controlled oxygen gradients. Mass spectrometry-based proteomics, including mass spectrometry imaging, offers opportunities for detecting, quantifying and understanding the roles of proteins and peptides, protein–protein interaction networks, and posttranslational modifications of proteins involved in hypoxia-associated biopathological processes. In this mini-review, we have summarized several modern approaches that are able to overcome the undesirable effects of hypoxia for breast cancer treatment. Thus, natural compounds with inhibitory effects on hypoxia-related signaling pathways in breast cancer cells and the tumor microenvironment, hyperbaric oxygen therapy, viral vector-based therapy that uses genetically engineered oncolytic viruses, and oncological bacteriotherapy based on biohybrid platforms, including anaerobic bacteria that are able to colonize inaccessible hypoxic regions in breast tumors to deliver chemotherapeutic drugs just into the tumor site, and smart nanoplatforms for abundant O2 generation within hypoxic breast cancer areas, including erythrocyte-like nanoparticles, metal-organic framework-nanoparticles, or engineered microalgae-metal-organic framework oxygenators, have been designed to relieve tumor hypoxia, induce antitumor responses, and improve the effects of traditional anti-breast cancer therapies.

摘要

乳腺癌是全球女性中最常被诊断出的癌症，也是导致癌症死亡的第二大原因。乳腺癌患者预后不良通常与瘤内缺氧区域的存在有关，这些区域由异常血管化和氧气供应不足引起，导致癌细胞能量危机；代谢和表观遗传重编程；参与血管生成的基因转录；癌细胞增殖；运动性、侵袭性和转移能力增强；突变积累；基因组不稳定性；干细胞特性的维持；基质细胞募集；细胞外基质重塑；慢性炎症；免疫逃逸；以及肿瘤微生物群的适应性反应。此外，缺氧通常与对单独或联合使用的传统抗肿瘤治疗的耐药性相关，这使得需要实施新的疗法来克服或减轻乳腺癌诊疗中氧缺乏的负面影响。在乳腺癌建模研究中，基于微纳加工的技术，包括乳腺癌芯片和乳腺癌转移芯片平台，能够在不同的可控氧梯度下重现乳腺癌的转移级联过程。基于质谱的蛋白质组学，包括质谱成像，为检测、量化和理解蛋白质和肽、蛋白质-蛋白质相互作用网络以及与缺氧相关的生物病理学过程中蛋白质翻译后修饰的作用提供了机会。在这篇小综述中，我们总结了几种能够克服缺氧对乳腺癌治疗不良影响的现代方法。因此，针对乳腺癌细胞及肿瘤微环境中缺氧相关信号通路具有抑制作用的天然化合物、高压氧治疗、使用基因工程溶瘤病毒的病毒载体疗法、基于生物杂交平台的肿瘤细菌疗法（包括能够定植于乳腺肿瘤难以到达的缺氧区域以将化疗药物直接递送至肿瘤部位的厌氧菌），以及用于在缺氧乳腺癌区域内生成充足氧气的智能纳米平台，包括红细胞样纳米颗粒、金属有机骨架纳米颗粒或工程化微藻-金属有机骨架制氧机，已被设计用于减轻肿瘤缺氧、诱导抗肿瘤反应，并改善传统抗乳腺癌治疗的效果。