背景:抗氧化剂机制的上调在癌细胞中很常见,因为它们努力保持平衡的氧化还原状态并防止氧化损伤。这包括胱氨酸/谷氨酸反转运蛋白xCT的上调,这在保护癌细胞免受氧化应激中起着至关重要的作用。因此,靶向xCT已经成为一种有吸引力的癌症治疗策略。然而,xCT也由几种类型的免疫细胞表达,其中它在增殖和效应子功能中起作用。鉴于这些观察,全面了解xCT在癌症发生和进展中的具体作用,以及它对肿瘤微环境中的免疫系统和抗肿瘤反应的潜在影响,需要进一步调查。
方法:我们制作了xCTnullBALB/c小鼠以研究xCT在免疫系统中的作用,并制作了xCTnull/Erbb2转基因BALB-neuT小鼠以研究xCT在乳腺癌易发模型中的作用。我们还使用来自BALB-neuT/xCTnull小鼠的乳腺癌细胞和xCTKO4T1细胞来测试xCT对体外和体内恶性特性的贡献。
结果:BALB-neuT/xCTnull小鼠的xCT耗竭不会改变自体肿瘤的发生,但是从这些小鼠中分离出的肿瘤细胞在体外表现出增殖和氧化还原平衡缺陷。尽管xCT破坏使4T1细胞对氧化应激敏感,它不能阻止可移植的肿瘤生长,但减少体外细胞迁移和体内肺转移。这伴随着转移前生态位中免疫细胞募集的改变。最后,在宿主小鼠中xCT的全身消耗不会影响可移植的肿瘤生长和转移,也不会损害体内体液和细胞免疫反应的适当建立。
结论:xCT对于适当的免疫系统功能是不必要的,从而支持xCT靶向在肿瘤学中的安全性。然而,xCT参与乳腺癌细胞转移种植所需的几个过程,从而扩大了xCT靶向方法的范围。
BACKGROUND: The upregulation of antioxidant mechanisms is a common occurrence in cancer cells, as they strive to maintain balanced redox state and prevent oxidative damage. This includes the upregulation of the cystine/glutamate antiporter xCT, which plays a crucial role in protecting cancer cells from oxidative stress. Consequently, targeting xCT has become an attractive strategy for cancer treatment. However, xCT is also expressed by several types of immune cells where it has a role in proliferation and effector functions. In light of these observations, a comprehensive understanding of the specific role of xCT in the initiation and progression of cancer, as well as its potential impact on the immune system within the tumor microenvironment and the anti-tumor response, require further investigation.
METHODS: We generated xCTnull BALB/c mice to investigate the role of xCT in the immune system and xCTnull/Erbb2-transgenic BALB-neuT mice to study the role of xCT in a mammary cancer-prone model. We also used mammary cancer cells derived from BALB-neuT/xCTnull mice and xCTKO 4T1 cells to test the contribution of xCT to malignant properties in vitro and in vivo.
RESULTS: xCT depletion in BALB-neuT/xCTnull mice does not alter autochthonous tumor initiation, but tumor cells isolated from these mice display proliferation and redox balance defects in vitro. Although xCT disruption sensitizes 4T1 cells to oxidative stress, it does not prevent transplantable tumor growth, but reduces cell migration in vitro and lung metastasis in vivo. This is accompanied by an altered immune cell recruitment in the pre-metastatic niche. Finally, systemic depletion of xCT in host mice does not affect transplantable tumor growth and metastasis nor impair the proper mounting of both humoral and cellular immune responses in vivo.
CONCLUSIONS: xCT is dispensable for proper immune system function, thus supporting the safety of xCT targeting in oncology. Nevertheless, xCT is involved in several processes required for the metastatic seeding of mammary cancer cells, thus broadening the scope of xCT-targeting approaches.