Tumor-Associated a2 Vacuolar ATPase Acts As a Key Mediator of Cancer-Related Inflammation by Inducing Pro-Tumorigenic Properties in Monocytes

Kwong, Christina; Gilman‐Sachs, Alice; Beaman, Kenneth D.

doi:10.4049/jimmunol.1002998

Cited by 38 publications

(70 citation statements)

References 63 publications

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“…Our previous studies showed that the key portion of the a2V protein is a2NTD, the N-terminal portion that is released from the activated monocyte and induces the cytokines secretion (Kwong et al 2011). In this study, we showed that capacitated sperm secrete a2NTD in the surrounding milieu.…”

Section: V-atpase Induces Immune Responses Of Pregnancysupporting

confidence: 49%

“…Previously, we have shown that a2V can regulate IL1B as well as IL1A with little or no subsequent increase in TNF secretion (Ntrivalas et al 2007, Kwong et al 2011. This process appears to occur by two different mechanisms.…”

Section: Introductionmentioning

confidence: 92%

“…The first is a2V expression on the cell surface, where it functions as an ATPase preventing the danger-associated molecular pattern (DAMP) ATP from activating the inflammasome through the P2X7 channel (Ntrivalas et al 2007). ATP binding to P2X7 causes the influx of potassium ions and the activation of the inflammasome (Kwong et al 2011). The second mechanism is the cleavage and release of soluble N-terminus portion (a2NTD) from a2V.…”

Section: Introductionmentioning

confidence: 99%

“…The second mechanism is the cleavage and release of soluble N-terminus portion (a2NTD) from a2V. This a2NTD peptide is responsible for the selective increase in transcription and secretion of several different cytokines and chemokines important in maintaining specific immune responses (Ntrivalas et al 2010, Kwong et al 2011.…”

Section: Introductionmentioning

confidence: 99%

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V-ATPase upregulation during early pregnancy: a possible link to establishment of an inflammatory response during preimplantation period of pregnancy

Jaiswal¹,

Mallers²,

Larsen³

et al. 2012

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104

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Various mechanisms exist to prevent a potentially deleterious maternal immune response that results in compromising survival of semiallogeneic fetus. In pregnancy, there is a necessary early preimplantation inflammatory stage followed by a postimplantation antiinflammatory stage. Thus, there is a biphasic 'immune response' observed during the course of pregnancy. We provide the evidence that capacitation of sperm induced the expression of a2 isoform of V-ATPase (ATP6V0A2 referred to as a2V), leukemia inhibitory factor (Lif), Il1b, and Tnf in the sperm. Capacitated sperm also released cleaved N-terminal domain of a2V-ATPase (a2NTD), which upregulates the gene expression of Lif, Il1b, Tnf, and monocyte chemotactic protein-1 (Ccl2 (Mcp1)) in the uterus. Unfertilized eggs had low a2V expression, but after fertilization, the expression of a2V increased in zygotes. This increased level of a2V expression was maintained in preimplantation embryos. Seminal plasma was necessary for upregulation of a2V expression in preimplantation embryos, as mating with seminal vesicle-deficient males failed to elicit an increase in a2V expression in preimplantation embryos. The infiltration of macrophages into the uterus was significantly increased after insemination of both sperm and seminal plasma during the preimplantation period of pregnancy. This dynamic infiltration into the uterus corresponded with the uterine a2V expression through the induction of Ccl2 expression. Furthermore, the polarization ratio of M1:M2 (pro-inflammatory/anti-inflammatory) macrophages in the uterus fluctuated from a ratio of 1.60 (day 1) to 1.45 (day 4) when female mice were inseminated with both sperm and seminal plasma. These data provide evidence that exposure to semen may initiate an inflammatory milieu by inducing a2V and cytokine/chemokine expression, which triggers the influx of macrophages into the preimplantation uterus during the onset of pregnancy and ultimately leads to successful pregnancy outcome.

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Section: V-atpase Induces Immune Responses Of Pregnancysupporting

confidence: 49%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

V-ATPase upregulation during early pregnancy: a possible link to establishment of an inflammatory response during preimplantation period of pregnancy

Jaiswal¹,

Mallers²,

Larsen³

et al. 2012

Reproduction

Self Cite

104

View full text Add to dashboard Cite

show abstract

“…Tumor cells consistently release immunosuppressive and proinflammatory factors that facilitate tumor immune-escape and tumor progression (20,21). In contrast, tumor-surrounding cells, such as dendritic cells, also secrete certain factors to modulate the development of cancer (22).…”

Section: Discussionmentioning

confidence: 99%

Lung Cancer-derived Galectin-1 Enhances Tumorigenic Potentiation of Tumor-associated Dendritic Cells by Expressing Heparin-binding EGF-like Growth Factor

Kuo

Huang

Cheng

et al. 2012

Journal of Biological Chemistry

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Background: Communication between cancer cells and immune cells in their microenvironment leads to cancer progression. Results: Lung cancer-derived galectin-1 stimulates HB-EGF expression and triggers a release mechanism in tumor-associated dendritic cells that stimulates tumor cell growth and invasion. Conclusion: The galectin-1/HB-EGF cycle between cancer and dendritic cells enhances lung cancer progression. Significance: Galectin-1 is a potential therapeutic target for inhibiting tumor-promoting immune cells in the tumor microenvironment.

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Cancer‐associated V‐ATPase induces delayed apoptosis of protumorigenic neutrophils

et al. 2020

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Tumors and neutrophils undergo an unexpected interaction, in which products released by tumor cells interact to support neutrophils that in turn support cancer growth, angiogenesis, and metastasis. A key protein that is highly expressed by cancer cells in tumors is the a2 isoform V‐ATPase (a2V). A peptide from a2V (a2NTD) is secreted specifically by cancer cells, but not normal cells, into the tumor microenvironment. This peptide reprograms neutrophils to promote angiogenesis, cancer cell invasiveness, and neutrophil recruitment. Here, we provide evidence that cancer‐associated a2V regulates the life span of protumorigenic neutrophils by influencing the intrinsic pathway of apoptosis. Immunohistochemical analysis of human cancer tissue sections collected from four different organs shows that levels of a2NTD and neutrophil counts are increased in cancer compared with normal tissues. Significant increases in neutrophil counts were present in both poorly and moderately differentiated tumors. In addition, there is a positive correlation between the number of neutrophils and a2NTD expression. Human neutrophils treated with recombinant a2NTD show significantly delayed apoptosis, and such prolonged survival was dependent on NF‐κB activation and ROS generation. Induction of antiapoptotic protein expression (Bcl‐xL and Bcl‐2A1) and decreased expression of proapoptotic proteins (Bax, Apaf‐1, caspase‐3, caspase‐6, and caspase‐7) were a hallmark of these treated neutrophils. Autocrine secretion of prosurvival cytokines of TNF‐α and IL‐8 by treated neutrophils prolongs their survival. Our findings highlight the important role of cancer‐associated a2V in regulating protumorigenic innate immunity, identifying a2V as a potential important target for cancer therapy.

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Tumor-Associated a2 Vacuolar ATPase Acts As a Key Mediator of Cancer-Related Inflammation by Inducing Pro-Tumorigenic Properties in Monocytes

Cited by 38 publications

References 63 publications

V-ATPase upregulation during early pregnancy: a possible link to establishment of an inflammatory response during preimplantation period of pregnancy

V-ATPase upregulation during early pregnancy: a possible link to establishment of an inflammatory response during preimplantation period of pregnancy

Lung Cancer-derived Galectin-1 Enhances Tumorigenic Potentiation of Tumor-associated Dendritic Cells by Expressing Heparin-binding EGF-like Growth Factor

Cancer‐associated V‐ATPase induces delayed apoptosis of protumorigenic neutrophils

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