Renal cell carcinoma as a cause of iron deficiency anemia

Dowd, Amar A.; Ibrahim, Faisal I.; Mohammed, Mutwkil M.

doi:10.1016/j.afju.2013.11.001

Cited by 8 publications

(7 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6 Mayo Clinic, Scottsdale, Arizona. tumorigenic factors such as cyclin D1, TGFa, and VEGFA (14,18). HIF-2a also potentiates protumorigenic c-Myc and b-catenin activity, which are inhibited by HIF-1a (19,20).…”

Section: Introductionmentioning

confidence: 99%

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

Cowman

Fuja

Liu

et al. 2020

Clinical Cancer Research

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Cowman

Fuja

Liu

et al. 2020

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Chromophobe RCCs can be differentiated from other RCCs based on the intense iron staining in the tumor tissue [80]. In addition, iron consumption by renal cell carcinoma has been considered as the cause of iron deficiency related anemia in patients [81, 82]. In cell culture models, the addition of iron to culture media sensitizes cancer cells to ferroptosis, probably by lowering the threshold to initiate oxidative damage [10].…”

Section: Connections To Human Diseasementioning

confidence: 99%

Ferroptosis: Death by Lipid Peroxidation

Yang

Stockwell

2016

Trends in Cell Biology

2,204

1,468

View full text Add to dashboard Cite

Ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and subsequent accumulation of lipid-based reactive oxygen species, particularly lipid hydroperoxides. This form of iron-dependent cell death is genetically, biochemically, and morphologically distinct from other cell death modalities, including apoptosis, unregulated necrosis, and necroptosis. Ferroptosis is regulated by specific pathways and is involved in diverse biological contexts. Here, we summarize the discovery of ferroptosis, the mechanism of ferroptosis regulation, and its increasingly appreciated relevance to both normal and pathological physiology.

show abstract

“…There are still no specific and reliable tumor markers neither for RCC diagnosis nor for monitoring post-operative disease outcome. Despite the apparent association of RCC with the development of systemic anemia in RCC patients [47], the role of iron in human RCC carcinogenesis is largely unknown and was only scarcely investigated so far. Because of the growing evidence on their tumor-promoting effects, the expression of iron-regulated genes could become an important factor among the markers of tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

The Disturbed Iron Phenotype of Tumor Cells and Macrophages in Renal Cell Carcinoma Influences Tumor Growth

Schnetz

Meier

Rehwald

et al. 2020

Cancers

View full text Add to dashboard Cite

Accumulating evidence suggests that iron homeostasis is disturbed in tumors. We aimed at clarifying the distribution of iron in renal cell carcinoma (RCC). Considering the pivotal role of macrophages for iron homeostasis and their association with poor clinical outcome, we investigated the role of macrophage-secreted iron for tumor progression by applying a novel chelation approach. We applied flow cytometry and multiplex-immunohistochemistry to detect iron-dependent markers and analyzed iron distribution with atomic absorption spectrometry in patients diagnosed with RCC. We further analyzed the functional significance of iron by applying a novel extracellular chelator using RCC cell lines as well as patient-derived primary cells. The expression of iron-regulated genes was significantly elevated in tumors compared to adjacent healthy tissue. Iron retention was detected in tumor cells, whereas tumor-associated macrophages showed an iron-release phenotype accompanied by enhanced expression of ferroportin. We found increased iron amounts in extracellular fluids, which in turn stimulated tumor cell proliferation and migration. In vitro, macrophage-derived iron showed pro-tumor functions, whereas application of an extracellular chelator blocked these effects. Our study provides new insights in iron distribution and iron-handling in RCC. Chelators that specifically scavenge iron in the extracellular space confirmed the importance of macrophage-secreted iron in promoting tumor growth.

show abstract

Renal cell carcinoma as a cause of iron deficiency anemia

Cited by 8 publications

References 9 publications

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

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

Ferroptosis: Death by Lipid Peroxidation

The Disturbed Iron Phenotype of Tumor Cells and Macrophages in Renal Cell Carcinoma Influences Tumor Growth

Contact Info

Product

Resources

About