Extravascular Red Blood Cells and Hemoglobin Promote Tumor Growth and Therapeutic Resistance as Endogenous Danger Signals

Yin, Tao; He, Sisi; Liu, Xiaoling; Ye, Tinghong; Lin, Ziqiang; Sang, Yaxiong; Su, Chao; Wan, Yang; Shen, Guobo; Ma, Xuelei; Yu, Min; Guo, Fuchun; Liu, Yanyang; Li, Ling; Hu, Quan; Wang, Yongsheng; Wei, Yuquan

doi:10.4049/jimmunol.1400643

Cited by 35 publications

(31 citation statements)

References 36 publications

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“…Complicated microenvironment in tumor results in high heterogeneity of HCC, making the therapeutic effect totally varied. TH in HCC implies tumor microenvironment of red blood cells releasing and platelet aggregation, which could promote tumor growth, invasion, and metastasis partially through the activation of NF-kB pathway [24] , [25] . The inflamed tumor microenvironment is another cause of tumor vessel injury [26] .…”

Section: Discussionmentioning

confidence: 99%

CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage

Wang

et al. 2018

Translational Oncology

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Spontaneous tumor hemorrhage (TH) is frequently observed in solid tumors including human hepatocellular carcinoma (HCC). TH implies fast-growing and worse tumor immunological microenvironment; however, the underlying mechanism remains largely unknown. CLEC1B is a signature gene highly associated with tumor progression. PD-L1 expression is a key biomarker predictive of immune checkpoint therapies, which showed astonishing effect on various types of tumor. We assume that, in HCC, TH may closely associate with the expression of these two molecules. In this study, 136 patients with HCC were enrolled. qRT-PCR showed that CLEC1B expression is significantly lower in HCC tumor tissue. Immunohistochemistry of HCC tissue microarrays demonstrated that PD-L1high and CLEC1Blow expressions were significantly correlated with TH and clinicopathological features indicating worse HCC progression. According to univariate/multivariate analysis, a combination of PD-L1high and CLEC1Blow expression was an independent prognostic factor indicating the poor outcome. The prognostic value of PD-L1high and CLEC1Blow was validated by Cox proportional-hazard analyses. Collectively, tumor with TH is closely associated with CLEC1Blow & PD-L1high expression, which may imply high response of PD-L1/PD-1 immune checkpoint therapies. CLEC1B may be a potential therapeutic target for PD-L1/PD-1 immunotherapy. PD-L1high and CLEC1Blow can be a valuable prognosis factor implying worse clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage

Wang

et al. 2018

Translational Oncology

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“…It is not even possible to discard that the expression of CD163 is an immune response to the extravascular hemoglobin content, secondary to necrosis index, eventually increased in tumors from patients receiving the combinatory treatment. Extravascular hemoglobin is a known endogenous danger signal that induces M2-skewed macrophage influx and CD163-macrophage polarization (61, 62). Clinically, CD163 + cell infiltration has been associated to both good (63) and bad (64–68) prognosis.…”

Section: Combining Bevacizumab With Immune Modulators To Enhance Antimentioning

confidence: 99%

Exploring the Immunological Mechanisms Underlying the Anti-vascular Endothelial Growth Factor Activity in Tumors

Aguiar

Moraes

2019

Front. Immunol.

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Several studies report the key role of the vascular endothelial growth factor (VEGF) signaling on angiogenesis and on tumor growth. This has led to the development of a number of VEGF-targeted agents to treat cancer patients by disrupting the tumor blood vessel supply. Of them, bevacizumab, an FDA-approved humanized monoclonal antibody against VEGF, is the most promising. Although the use of antibodies targeting the VEGF pathway has shown clinical benefits associated with a reduction in the tumor blood vessel density, the inhibition of VEGF-driven vascular effects is only part of the functional mechanism of these therapeutic agents in the tumor ecosystem. Compelling reports have demonstrated that VEGF confers, in addition to the activation of angiogenesis-related processes, immunosuppressive properties in tumors. It is also known that structural remodeling of the tumor blood vessel bed by anti-VEGF approaches affect the influx and activation of immune cells into tumors, which might influence the therapeutic results. Besides that, part of the therapeutic effects of antiangiogenic antibodies, including their role in the tumor vascular network, might be triggered by Fc receptors in an antigen-independent manner. In this mini-review, we explore the role of VEGF inhibitors in the tumor microenvironment with focus on the immune system, discussing around the functional contribution of both bevacizumab's Fab and Fc domains to the therapeutic results and the combination of bevacizumab therapy with other immune-stimulatory settings, including adjuvant-based vaccine approaches.

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“…This is because the vast stoichiometric excess of the high affinity heme scavenger protein hemopexin that is present in the plasma (Schaer et al, 2013) would quickly sequester any heme that enters the blood stream from the gut. In addition, heme derivatives released locally from damaged red blood cells within the abnormal neovasculature of cancers (Yin et al, 2015) and atheromas (Balla et al, 2007) seem much more likely to serve as the main sources of heme oxidant compounds in tissues throughout the body. Indeed, it is reported that the interior of advanced atheromatous lesions functions as a pro-oxidant environment in which erythrocytes breakdown and release both heme and iron to promote further lipid oxidation, thereby amplifying endothelial cell cytotoxicity (Balla et al, 1991; Balla et al, 1993; Belcher et al, 1993; Nagy et al, 2010).…”

Section: Existing Theories To Explain Increased Disease Risks Of Rmentioning

confidence: 99%

Human risk of diseases associated with red meat intake: Analysis of current theories and proposed role for metabolic incorporation of a non-human sialic acid

Alisson-Silva

Kawanishi

Varki

2016

Molecular Aspects of Medicine

130

103

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One of the most consistent epidemiological associations between diet and human disease risk is the impact of red meat consumption (beef, pork, and lamb, particularly in processed forms). While risk estimates vary, associations are reported with all-cause mortality, colorectal and other carcinomas, atherosclerotic cardiovascular disease, type II diabetes, and possibly other inflammatory processes. There are many proposed explanations for these associations, some long discussed in the literature. Attempts to explain the effects of red meat consumption have invoked various red meat-associated agents, including saturated fat, high salt intake, Trimethylamine–N-oxide (TMAO) generation by microbiota, and environmental pollutants contaminating red meat, none of which are specific for red meat. Even the frequently mentioned polycyclic aromatic carcinogens arising from high temperature cooking methods are not red meat specific, as these are also generated by grilling poultry or fish, as well as by other forms of cooking. The traditional explanations that appear to be more red meat specific invoke the impact of N-nitroso compounds, heme iron, and the potential of heme to catalyze endogenous nitrosation. However, heme can be denatured by cooking, high levels of plasma hemopexin will block its tissue delivery, and much higher amounts of heme likely originate from red blood cell breakdown in vivo. Therefore, red meat-derived heme could only contribute to colorectal carcinoma risk, via direct local effects. Also, none of these mechanisms explain the apparent human propensity i.e., other carnivores have not been reported at high risk for all these diseases. A more recently proposed hypothesis involves infectious agents in beef from specific dairy cattle as agents of colorectal cancer. We have also described another mechanistic explanation for the human propensity for risk of red-meat associated diseases that is consistent with most observations: metabolic incorporation of a non-human sialic acid N-glycolylneuraminic acid (Neu5Gc) into the tissues of red meat consumers and the subsequent interaction with inflammation-provoking antibodies against this “xenoautoantigen”. Overall, we conclude that while multiple mechanisms are likely operative, many proposed theories to date are not specific for red meat, and that the viral and xenoautoantigen theories deserve further consideration. Importantly, there are potential non-toxic dietary antidotes, if the xenoautoantigen is indeed correct.

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Extravascular Red Blood Cells and Hemoglobin Promote Tumor Growth and Therapeutic Resistance as Endogenous Danger Signals

Cited by 35 publications

References 36 publications

CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage

CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage

Exploring the Immunological Mechanisms Underlying the Anti-vascular Endothelial Growth Factor Activity in Tumors

Human risk of diseases associated with red meat intake: Analysis of current theories and proposed role for metabolic incorporation of a non-human sialic acid

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