Macrophage HIF-1α Is an Independent Prognostic Indicator in Kidney Cancer

Abstract

Purpose: Clear cell renal cell carcinoma (ccRCC) is frequently associated with inactivation of the von Hippel-Lindau tumor suppressor, resulting in activation of HIF-1a and HIF-2a. The current paradigm, established using mechanistic cell-based studies, supports a tumor promoting role for HIF-2a, and a tumor suppressor role for HIF-1a. 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.Experimental Design: 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 IHC.Results: HIF-1a was primarily expressed in tumor-associated macrophages (TAMs), whereas HIF-2a and HAF were expressed primarily in tumor cells. TAM-associated HIF-1a was significantly associated with high tumor grade and increased metastasis and was independently associated with decreased overall survival. Furthermore, elevated TAM HIF-1a was significantly associated with resistance to antiangiogenic therapy. In contrast, high HAF or HIF-2a were associated with low grade, decreased metastasis, and increased overall survival. scRNA-seq, RNA-ISH, and Western blotting confirmed the expression of HIF-1a in M2-polarized CD163-expressing TAMs.Conclusions: These findings highlight a potential role of TAM HIF-1a in ccRCC progression and support the reevaluation of HIF-1a as a therapeutic target and marker of disease progression.

Exosome-mediated communication between tumor cells and tumor-associated macrophages: implications for tumor microenvironment

“…Some studies have shown that the number of TAMs infiltrating tissue is closely related to the vascular density in tumors. 120 , 121 Large aggregates of TAMs were found in anoxic areas, especially in necrotic tissues. 122 TAMs are regarded as significant producers of proangiogenic factors in malignant tumors because they release IL-1β, VEGF, TNF-α, and other cytokines.…”

Spatial Clustering of CD68+ Tumor Associated Macrophages with Tumor Cells is Associated with Worse Overall Survival in Metastatic Clear Cell Renal Cell Carcinoma

“…Tumor-associated macrophages (TAM) activate oncogenic signaling and facilitate tumor growth and progression by secreting cytokines, growth factors, and angiogenic mediators, as well as a variety of proteases that activate additional growth factors and angiogenic mediators embedded in the extracellular matrix [7][8][9][10][11][12][13][14] . These paracrine interactions are concentration-gradient-dependent, and as such, the underlying biology may be better reflected by measures of local cellular clustering as opposed to global density metrics.…”

“…These paracrine interactions are concentration-gradient-dependent, and as such, the underlying biology may be better reflected by measures of local cellular clustering as opposed to global density metrics. Prior work has demonstrated an association between TAM density and worse overall survival (OS) in patients with clear cell renal cell carcinoma (ccRCC), but none have assessed TAM cellular clustering 9,12,14,15 .…”

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

“…The study revealed that overexpression of cytoplasmic HIF1α is associated with a higher nuclear grade, larger tumor size, higher stage and shorter survival, while nuclear HIF1α overexpression is associated with better diagnostic parameters (i.e., lower nuclear grade, smaller tumor size and longer survival) [ 73 ]. However, a recent comprehensive study revealed that macrophage HIF1α appears to be an independent prognostic indicator for ccRCC [ 74 ]. These authors used a large cohort of ccRCC tumor tissues (380 on a tissue microarray, an additional 57 ccRCC from patients treated with antiangiogenic therapy for response associations analysis) to assess the expression of HAF (hypoxia-associated factor, which regulates HIFs), HIF1α and HIF2α in ccRCC.…”

“…These authors used a large cohort of ccRCC tumor tissues (380 on a tissue microarray, an additional 57 ccRCC from patients treated with antiangiogenic therapy for response associations analysis) to assess the expression of HAF (hypoxia-associated factor, which regulates HIFs), HIF1α and HIF2α in ccRCC. The study revealed that HIF1α was primarily expressed in tumor-associated macrophages (TAM), whereas HIF2α and HAF were mainly expressed in tumor cells [ 74 ]. TAM-associated HIF1α was significantly associated with high tumor grade and increased metastasis and was independently associated with decreased overall survival [ 74 ].…”