Macrophage HIF-1α Is an Independent Prognostic Indicator in Kidney Cancer
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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-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. 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-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. Furthermore, elevated TAM HIF-1α was significantly associated with resistance to antiangiogenic therapy. In 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. Conclusions: These findings highlight a potential role of TAM HIF-1α in ccRCC progression and support the reevaluation of HIF-1α as a therapeutic target and marker of disease progression.
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HIF-1α or HIF-2α expression in TAMs is associated with tumor progression and/or poor prognosis in multiple tumor types.
“Both HIF-1α or HIF-2α expression in TAMs have been associated with tumor progression and/or poor prognosis in multiple tumor types, whereas lack of HIF-1α or HIF-2α in TAMs decreases metastasis, cell proliferation, and expression of pro-inflammatory cytokines such as IL-6 [73–76].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [73]
The Abstract Results and Discussion report that HIF-1α in tumor-associated macrophages is associated with progression and poorer survival in clear-cell kidney cancer. They do not establish this association across multiple tumor types. The Abstract Results instead locate HIF-2α primarily in tumor cells and associate higher HIF-2α with better outcomes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLack of HIF-1α or HIF-2α in TAMs decreases metastasis, cell proliferation, and expression of pro-inflammatory cytokines such as IL-6.
“Both HIF-1α or HIF-2α expression in TAMs have been associated with tumor progression and/or poor prognosis in multiple tumor types, whereas lack of HIF-1α or HIF-2α in TAMs decreases metastasis, cell proliferation, and expression of pro-inflammatory cytokines such as IL-6 [73–76].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [73]
The Abstract Results associate TAM HIF-1α with increased metastasis, and the Results find inflammatory-response pathways enriched in HIF1A-positive macrophages. The paper does not show that loss of either HIF isoform in TAMs decreases metastasis, cell proliferation, or IL-6 expression; the Discussion also says macrophage-specific HIF-2α was not detected in the kidney tumors examined. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn that model, HIF-1α deletion prevented tumor formation, while HIF-2α deletion only moderately affected tumor onset.
“In this model, HIF-1α deletion abrogated tumor formation whereas HIF-2α deletion had only moderate effects on tumor onset [33].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [33]
The Introduction (page unavailable) discusses HIF1A deletion in high-grade kidney tumors and HIF-1α expression in early lesions, but does not describe the claimed deletion experiment. Searches for tumor formation, tumor onset, and HIF-1α/HIF-2α knockout found no passage comparing their effects in that model. (LLM, conf=0.72)
Experimental — accuracy not yet measuredIn vitro HIF-1α knockdown in the same genetic context did not affect in vitro or in vivo allograft growth, highlighting the importance of physiological context for HIF isoform contributions to ccRCC.
“Strikingly, in vitro HIF-1α knockdown within this same genetic context had no effect on in vitro or in vivo allograft growth, underscoring the importance of physiological context in determining the contribution of the HIF isoforms to ccRCC development and progression [33].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [33]
The Results describe HIF-1α expression in ccRCC cells and tumor-associated macrophages, and the Discussion considers how the tumor microenvironment affects that expression. Neither section reports HIF-1α knockdown or its effects on in vitro growth or in vivo allograft growth (searched: knockdown, allograft). (LLM, conf=0.76)
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References 46 · Cited by 76
Research works printed but not linked: 1
- [28]Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M, Signoretti S, Genetic and functional studies implicate HIF1alpha as a 14q kidney cancer suppressor gene. Cancer Discov 2011; 1(3): 222– 35 doi 2159–8290.CD-11–0098 [pii] 10.1158/2159-8290.CD-11-0098. 22037472 PMC3202343 · DOI · Paper page
- Authors
- Cowman, S. J., Fuja, D. G., Liu, X.-D., Tidwell, R. S. S., Kandula, N., Sirohi, D., Agarwal, A. M., Emerson, L. L., Tripp, S. R., Mohlman, J. S., Stonhill, M., Garcia, G., Conley, C. J., Olalde, A. A., Sargis, T., Ramirez-Torres, A., Karam, J. A., Wood, C. G., Sircar, K., Tamboli, P., Boucher, K., Maughan, B., Spike, B. T., Ho, T. H., Agarwal, N., Jonasch, E., & Koh, M. Y.
- Affiliations
- University of Utah (US)
- The University of Texas MD Anderson Cancer Center (US)
- ARUP Institute for Clinical and Experimental Pathology (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- 5Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
- Mayo Clinic in Arizona (US)
- Corresponding author
- Koh, Mei Yee
- ORCID
- Cowman, Sophie J.
- Fuja, Daniel G.
- Liu, Xian-De
- Tidwell, Rebecca S. Slack
- Sirohi, Deepika
- Agarwal, Archana M.
- Emerson, Lyska L.
- Tripp, Sheryl R.
- Stonhill, Miekan
- Conley, Christopher J.
- Olalde, Adam A.
- Karam, Jose A.
- Wood, Christopher G.
- Sircar, Kanishka
- Boucher, Kenneth
- Maughan, Benjamin
- Spike, Benjamin T.
- Ho, Thai H.
- Agarwal, Neeraj
- Jonasch, Eric
- Koh, Mei Yee
- Venue
- Clinical Cancer Research
- Published
- 2020-09-15
- Volume
- 26
- Issue
- 18
- Pages
- 4970-4982
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC7968518
- OpenAlex
- W3037831638
- Cited by
- 76
- References
- 46
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 15 · 2023: 25 · 2022: 11 · 2021: 9
- FWCI
- 6.47
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-06-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH
- NCI (CA181106, CA217905, R01CA224917, P30CA042014, P30CA016672)
- the Huntsman Cancer Institute at the University of Utah
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- HIF-1α, HIF-2α, clear cell renal cell carcinoma, tumor-associated macrophages, prognostic factors, anti-angiogenic therapy resistance, CD163, M2 macrophage polarization, metastasis, overall survival, tumor grade
- MeSH terms
- RNA-Seq, Tumor-Associated Macrophages, Endothelial PAS Domain-Containing Protein 1, Adult, Aged, Aged, 80 and over, Carcinoma, Renal Cell, Female, Humans, Kidney Neoplasms, Male, Middle Aged, Neoplasm Staging, Nephrectomy, Prognosis, Retrospective Studies, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Survival Analysis, Genes, Tumor Suppressor, Chemotherapy, Adjuvant, Disease Progression, Cell Line, Tumor, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Single-Cell Analysis, Neoplasm Grading
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