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Progression of luminal breast tumors is promoted by menage a trois between the inflammatory cytokine TNF? and the hormonal and growth-supporting arms of the tumor microenvironment.

ABSTRACT: Breast cancer progression is strongly linked to inflammatory processes, aggravating disease course. The impacts of the inflammatory cytokine TNF ? on breast malignancy are not fully substantiated, and they may be affected by cooperativity between TNF ? and other protumoral mediators. Here, we show that together with representatives of other important arms of the tumor microenvironment, estrogen (hormonal) and EGF (growth-supporting), TNF ? potently induced metastasis-related properties and functions in luminal breast tumor cells, representing the most common type of breast cancer. Jointly, TNF? + Estrogen + EGF had a stronger effect on breast cancer cells than each element alone, leading to the following: (1) extensive cell spreading and formation of FAK/paxillin-enriched cellular protrusions; (2) elevated proportion of tumor cells coexpressing high levels of CD44 and ? 1 and VLA6; (3) EMT and cell migration; (4) resistance to chemotherapy; (5) release of protumoral factors (CXCL8, CCL2, MMPs). Importantly, the tumor cells used in this study are known to be nonmetastatic under all conditions; nevertheless, they have acquired high metastasizing abilities in vivo in mice, following a brief stimulation by TNF? + Estrogen + EGF. These dramatic findings indicate that TNF ? can turn into a strong prometastatic factor, suggesting a paradigm shift in which clinically approved inhibitors of TNF? would be applied in breast cancer therapy.

SUBMITTER: Weitzenfeld P

PROVIDER: S-EPMC3867893 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Progression of luminal breast tumors is promoted by ménage à trois between the inflammatory cytokine TNFα and the hormonal and growth-supporting arms of the tumor microenvironment.

Weitzenfeld Polina P Meron Nurit N Leibovich-Rivkin Tal T Meshel Tsipi T Ben-Baruch Adit A

Mediators of inflammation 20131204

Breast cancer progression is strongly linked to inflammatory processes, aggravating disease course. The impacts of the inflammatory cytokine TNF α on breast malignancy are not fully substantiated, and they may be affected by cooperativity between TNF α and other protumoral mediators. Here, we show that together with representatives of other important arms of the tumor microenvironment, estrogen (hormonal) and EGF (growth-supporting), TNF α potently induced metastasis-related properties and funct ...[more]

PMID: 24369447

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Project description:BackgroundAlthough Campylobacter jejuni-infections have a high prevalence worldwide and represent a significant socioeconomic burden, it is still not well understood how C. jejuni causes intestinal inflammation. Detailed investigation of C. jejuni-mediated intestinal immunopathology is hampered by the lack of appropriate vertebrate models. In particular, mice display colonization resistance against this pathogen.Methodology/principal findingsTo overcome these limitations we developed a novel C. jejuni-infection model using gnotobiotic mice in which the intestinal flora was eradicated by antibiotic treatment. These animals could then be permanently associated with a complete human (hfa) or murine (mfa) microbiota. After peroral infection C. jejuni colonized the gastrointestinal tract of gnotobiotic and hfa mice for six weeks, whereas mfa mice cleared the pathogen within two days. Strikingly, stable C. jejuni colonization was accompanied by a pro-inflammatory immune response indicated by increased numbers of T- and B-lymphocytes, regulatory T-cells, neutrophils and apoptotic cells, as well as increased concentrations of TNF-α, IL-6, and MCP-1 in the colon mucosa of hfa mice. Analysis of MyD88(-/-), TRIF(-/-), TLR4(-/-), and TLR9(-/-) mice revealed that TLR4- and TLR9-signaling was essential for immunopathology following C. jejuni-infection. Interestingly, C. jejuni-mutant strains deficient in formic acid metabolism and perception induced less intestinal immunopathology compared to the parental strain infection. In summary, the murine gut flora is essential for colonization resistance against C. jejuni and can be overcome by reconstitution of gnotobiotic mice with human flora. Detection of C. jejuni-LPS and -CpG-DNA by host TLR4 and TLR9, respectively, plays a key role in immunopathology. Finally, the host immune response is tightly coupled to bacterial formic acid metabolism and invasion fitness.Conclusion/significanceWe conclude that gnotobiotic and "humanized" mice represent excellent novel C. jejuni-infection and -inflammation models and provide deep insights into the immunological and molecular interplays between C. jejuni, microbiota and innate immunity in human campylobacteriosis.

Dataset Information

Progression of luminal breast tumors is promoted by menage a trois between the inflammatory cytokine TNF? and the hormonal and growth-supporting arms of the tumor microenvironment.

Publications

Progression of luminal breast tumors is promoted by ménage à trois between the inflammatory cytokine TNFα and the hormonal and growth-supporting arms of the tumor microenvironment.

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