PTX3 Is an Extrinsic Oncosuppressor Regulating Complement-Dependent Inflammation in Cancer

Bonavita, Eduardo; Gentile, Stefania; Rubino, Marcello; Maina, Virginia; Papait, Roberto; Kunderfranco, Paolo; Greco, Carolina; Feruglio, F.; Molgora, Martina; Laface, Ilaria; Tartari, Silvia; Doni, Andrea; Pasqualini, Fabio; Barbati, Elisa; Basso, Gianluca; Galdiero, Maria Rosaria; Nebuloni, Manuela; Roncalli, Massimo; Colombo, Piergiuseppe; Laghi, Luigi; Lambris, John D.; Jaillon, Sébastien; Garlanda, Cecília; Mantovani, Alberto

doi:10.1016/j.cell.2015.01.004

Cited by 351 publications

(385 citation statements)

References 57 publications

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“…In contrast to C5aR, which has been reported to act via induction of MDSC and inhibition of CD8 + CTL responses (6), we show that C3aR deficiency/antagonism leads to a reduction in tumor-associated macrophages, along with increased neutrophil and CD4 + T cell populations. Macrophages are an essential component of tumor-promoting inflammation, and reduced tumor growth in C3-deficient mice has recently been associated with a reduction in tumor-associated macrophages (25). However, this same group showed that the reduction in macrophages was not sufficient to completely ablate tumor susceptibility, suggesting the involvement of other cells or mechanisms.…”

Section: Discussionmentioning

confidence: 98%

“…Complement is now thought to be a key component of cancer-related inflammation, and a recent study has suggested that exacerbated inflammation in the tumor microenvironment promotes genetic instability (25). The canonical proinflammatory mediator C5a has been widely implicated for a role in tumor growth, with both tumor-promoting and tumor-inhibitory effects reported, depending on tumor type, immune status of the host, and C5a levels (6)(7)(8)(9)26).…”

Section: Discussionmentioning

confidence: 99%

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The Complement C3a Receptor Contributes to Melanoma Tumorigenesis by Inhibiting Neutrophil and CD4+ T Cell Responses

Nabizadeh

Manthey

Steyn

et al. 2016

The Journal of Immunology

102

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The complement peptide C3a is a key component of the innate immune system and a major fragment produced following complement activation. We used a murine model of melanoma (B16-F0) to identify a hitherto unknown role for C3a–C3aR signaling in promoting tumor growth. The results show that the development and growth of B16-F0 melanomas is retarded in mice lacking C3aR, whereas growth of established melanomas can be arrested by C3aR antagonism. Flow cytometric analysis showed alterations in tumor-infiltrating leukocytes in the absence of C3aR. Specifically, neutrophils and CD4+ T lymphocyte subpopulations were increased, whereas macrophages were reduced. The central role of neutrophils was confirmed by depletion experiments that reversed the tumor inhibitory effects observed in C3aR-deficient mice and returned tumor-infiltrating CD4+ T cells to control levels. Analysis of the tumor microenvironment showed upregulation of inflammatory genes that may contribute to the enhanced antitumor response observed in C3aR-deficient mice. C3aR deficiency/inhibition was also protective in murine models of BRAFV600E mutant melanoma and colon and breast cancer, suggesting a tumor-promoting role for C3aR signaling in a range of tumor types. We propose that C3aR activation alters the tumor inflammatory milieu, thereby promoting tumor growth. Therapeutic inhibition of C3aR may therefore be an effective means to trigger an antitumor response in melanoma and other cancers.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

The Complement C3a Receptor Contributes to Melanoma Tumorigenesis by Inhibiting Neutrophil and CD4+ T Cell Responses

Nabizadeh

Manthey

Steyn

et al. 2016

The Journal of Immunology

102

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“…These studies showed that complement promotes growth and expansion of malignant tumors. Bonavita et al showed that complement promotes malignant transformation of cells exposed to chronic inflammation induced by chemical carcinogens (39). However, additional studies are required to dissect the effect of early versus late stages of complement activation on various stages of oncogenesis.…”

Section: Complement and Cancermentioning

confidence: 99%

The role of the complement system in cancer

Afshar-Kharghan¹

2017

Journal of Clinical Investigation

409

302

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“…Colon tumor cell secretion of the C-C family chemokine, CCL2, was essential for tumorigenesis through recruitment and activation of protumorigenic myeloid cells (40). Pentraxin 3 (PTX3) is a tumor suppressor that activates complement-mediated antitumor immunity and is epigenetically silenced due to methylation in colon tumors (41) …”

Section: Hypoxia and Epithelial-elicited Tumor Inflammatory Responsementioning

confidence: 99%

Hypoxia-inducible factors: a central link between inflammation and cancer

Triner

Shah²

2016

Journal of Clinical Investigation

160

126

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PTX3 Is an Extrinsic Oncosuppressor Regulating Complement-Dependent Inflammation in Cancer

Abstract: A commentary on PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer by Bonavita E, Gentile S, Rubino M, Maina V, Papait R, Kunderfranco P, et al.

Cited by 351 publications

References 57 publications

The Complement C3a Receptor Contributes to Melanoma Tumorigenesis by Inhibiting Neutrophil and CD4+ T Cell Responses

The Complement C3a Receptor Contributes to Melanoma Tumorigenesis by Inhibiting Neutrophil and CD4+ T Cell Responses

The role of the complement system in cancer

Hypoxia-inducible factors: a central link between inflammation and cancer

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