Macrophage HIF-1α Is an Independent Prognostic Indicator in Kidney Cancer.
Macrophage HIF-1α Is an Independent Prognostic Indicator in Kidney Cancer.
复制标题
巨噬细胞HIF-1α是肾癌的独立预后指标。
DOI：
10.1158/1078-0432.ccr-19-3890
复制
发表时间：
2020-09-15
期刊：
影响因子：
--
通讯作者：
Koh MY
中科院分区：
文献类型：
--
作者：
Cowman SJ;Fuja DG;Liu XD;Tidwell RSS;Kandula N;Sirohi D;Agarwal AM;Emerson LL;Tripp SR;Mohlman JS;Stonhill M;Garcia G;Conley CJ;Olalde AA;Sargis T;Ramirez-Torres A;Karam JA;Wood CG;Sircar K;Tamboli P;Boucher K;Maughan B;Spike BT;Ho TH;Agarwal N;Jonasch E;Koh MY
肾透明细胞癌（ccRCC）通常与von Hippel Lindau肿瘤抑制因子失活相关，导致HIF-1α和HIF-2α活化。目前的模式，建立了基于细胞的机制研究，支持肿瘤促进作用的HIF-2α，和肿瘤抑制作用的HIF-1α。然而，很少有研究全面研究了这种模式的临床意义。此外，调节HIF的缺氧相关因子（HAF）尚未在ccRCC中进行全面评估。为了评估HAF/HIF在ccRCC中的参与，我们使用来自380名患者的组织分析了它们与肿瘤分级/分期/结局的关系，并使用来自另外72名患者的组织和另外57名接受抗血管生成治疗的患者的组织验证了这些相关性。使用单细胞mRNA测序（scRNA-seq）、RNA原位杂交（RNA-ISH）和免疫组织化学进行进一步表征。HIF-1α主要表达于肿瘤相关巨噬细胞（TAMs），而HIF-2α和HAF主要表达于肿瘤细胞。TAM相关HIF-1α与高肿瘤分级和转移增加显著相关，与总生存率降低独立相关。此外，TAM HIF-1α升高与抗血管生成治疗的抵抗显著相关。相反，高HAF或HIF-2α与低级别、转移减少和总生存率增加相关。ScRNA-seq、RNA-ISH和Western blotting证实了HIF-1α在表达M2极化CD 163的TAM中的表达。这些发现强调了TAM HIF-1α在ccRCC进展中的潜在作用，并支持重新评估HIF-1α作为治疗靶点和疾病进展标志物。
Clear cell renal cell carcinoma (ccRCC) is frequently associated with inactivation of the von Hippel Lindau tumor suppressor, resulting in activation of HIF-1α and HIF-2α. The current paradigm, established using mechanistic cell-based studies, supports a tumor promoting role for HIF-2α, and a tumor suppressor role for HIF-1α. However, few studies have comprehensively examined the clinical relevance of this paradigm. Furthermore, the hypoxia associated factor (HAF), which regulates the HIFs, has not been comprehensively evaluated in ccRCC. To assess the involvement of HAF/HIFs in ccRCC, we analyzed their relationship to tumor grade/stage/outcome using tissue from 380 patients, and validated these associations using tissue from 72 additional patients and a further 57 patients treated with antiangiogenic therapy for associations with response. Further characterization was performed using single cell mRNA sequencing (scRNA-seq), RNA-in situ hybridization (RNA-ISH) and immunohistochemistry. HIF-1α was primarily expressed in tumor-associated macrophages (TAMs), whereas HIF-2α and HAF were expressed primarily in tumor cells. TAM-associated HIF-1α was significantly associated with high tumor grade and increased metastasis and was independently associated with decreased overall survival. Further, elevated TAM HIF-1α was significantly associated with resistance to antiangiogenic therapy. By contrast, high HAF or HIF-2α were associated with low grade, decreased metastasis and increased overall survival. ScRNA-seq, RNA-ISH and Western blotting confirmed the expression of HIF-1α in M2-polarized CD163 expressing TAMs. These findings highlight a potential role of TAM HIF-1α in ccRCC progression and support the re-evaluation of HIF-1α as a therapeutic target and marker of disease progression.