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Molecular Cancer Research
Molecular Cancer Research

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Cancer and the Complement Cascade

Martin J. Rutkowski, Michael E. Sughrue, Ari J. Kane, Steven A. Mills and Andrew T. Parsa
Martin J. Rutkowski
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Michael E. Sughrue
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Ari J. Kane
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Steven A. Mills
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Andrew T. Parsa
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DOI: 10.1158/1541-7786.MCR-10-0225 Published November 2010
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  • FIGURE 1.
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    FIGURE 1.

    The complement cascade. The complement cascade comprises the classic, alternative, and MBL pathways. The classic pathway is activated by the Fc portion of immunoglobulins bound to antigen, apoptotic cells, Gram-negative bacteria, and viruses. The C1 complex, made up of C1q, C1r, and C1s subunits, initiates the downstream classic cascade. Upon binding of C1q to an inciting stimulus, C1r catalyzes breakage of a C1s ester bond, resulting in its activation and subsequent cleavage of C2 and C4 into their respective “a” and “b” fragments. The formation of C2a4b creates C3 convertase, which cleaves C3 into C3a and C3b. C3b binds to other C3 convertases, forming C2a4b3b, also known as C5 convertase. It facilitates the final steps of the cascade by splitting C5 into C5a and C5b. The latter fragment is the critical first protein that combines with C6, C7, C8, and multiple C9 proteins to form the MAC, the terminal, pore-forming complement protein complex responsible for lysis of cells and pathogens. The MBL pathway is activated by surfaces bearing mannose groups or other pathogen-associated molecular patterns. MBL or ficolin activation of mannose-associated serine proteases (MASP) results in cleavage of C2 and C4 similar to the C1 complex, with subsequent production of C3 convertase and complement cascade activation resembling the classic pathway. Lastly, the alternative pathway is activated by a multitude of infectious agents including various bacteria, viruses, and fungi, as well as neoplastic cells. This pathway exhibits a unique “tickover” effect whereby low-level C3 cleavage occurs continuously. Generated C3b binds Bb, a cleavage fragment of factor B, and properdin, resulting in the formation of the alternative pathway C3 convertase. Binding of additional C3b to the alternative pathway C3 convertase renders it capable of C5 cleavage, and forms the basis for the amplification loop of the alternative pathway. Additionally, C3b generated by alternative pathway C3 convertase can attach to target surfaces and bind Bb, forming a C3 convertase that amplifies downstream complement proteins locally at the target surface. Although the activation and amplification of the three pathways differ initially, they commonly cleave C3 into C3a and C3b, resulting in terminal formation of the MAC.

  • FIGURE 2.
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    FIGURE 2.

    Potential oncogenic roles for complement proteins. Complement proteins contribute to each major hallmark of cancer, including mitogenic signaling cascades and growth factor production, angiogenesis, protection from antigrowth signals and apoptosis, cellular invasion and migration through the extracellular matrix, and suppression of antitumor immunity.

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  • Table 1.

    The specific contributions of various complement proteins to neoplastic phenomena

    Complement proteinTumorigenic effectTumorigenic hallmark
    C1qExtracellular matrix anchoringInvasion and migration
    C1sExtracellular matrix disintegrationInvasion and migration
    Activation of MMP-9Invasion and migration
    C3Production of VEGFAngiogenesis
    Extracellular matrix reorganizationInvasion and migration
    Extracellular matrix disintegrationInvasion and migration
    C3aActivation of ERK1/2, AktMitogenesis
    Induction of IL-6Growth factor/cytokine production
    Production of VEGFAngiogenesis
    Extracellular matrix reorganizationInvasion and migration
    Cellular chemotaxisInvasion and migration
    C3dExtracellular matrix anchoringInvasion and migration
    Factor BExtracellular matrix disintegrationInvasion and migration
    C5Induction of TGF-β, IGFs, IGFBPsGrowth factor/cytokine production
    Extracellular matrix disintegrationInvasion and migration
    C5aActivation of ERK1/2, Akt, JNK, p38 MAPK, phospholipase C β-2, phospholipase D, MEK-1, PKC, NF-κBMitogenesis
    Stimulation of HGF, c-MET receptorGrowth factor/cytokine production
    Transactivation of EGFRMitogenesis, cellular migration
    Induction of cyclin E, D1Mitogenesis
    Induction of IL-6Growth factor/cytokine production
    Inhibition of caspase-3Prevention of apoptosis
    Production of VEGFAngiogenesis
    Cellular chemotaxisInvasion and migration
    Inhibition of CD8+ T cellsAntitumor Immunosuppression
    MDSC migration and production of ROS/RNSAntitumor immunosuppression
    C9Extracellular matrix disintegrationInvasion and migration
    MACInduction of CDK 2 and 4, p21, RGC-32Mitogenesis
    Activation of ERK, p38 MAPK, JNK, PI3K, Ras, p70 S6 kinase, JAK-STATMitogenesis
    Activation of c-jun, junD, c-fosMitogenesis
    Induction of bFGF, PDGF, TGF-βGrowth factor/cytokine production, angiogenesis
    Inhibition of caspase-3, caspase-8, BAD, BID, TNF-α, FasLPrevention of apoptosis
    Induction of bcl-2, IGF-IPrevention of apoptosis
    Production of VEGFAngiogenesis

    Abbreviations: BAD, bcl-xL/bcl-2–associated death promoter; Bcl-2, B-cell lymphoma-2; bFGF, basic fibroblast growth factor; BID, bcl-2 interacting domain; CDK, cyclin-dependent kinase; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FasL, Fas ligand; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; IL-6, interleukin-6; JAK-STAT, Janus activated kinase–signal transducer and activated transcription; JNK, c-jun amino terminal kinase; MAPK, mitogen-activated protein kinase; MDSC, myeloid-derived suppressor cells; MEK-1, mitogen-activated protein kinase or ERK kinase-1; METr, mesenchymal-epithelial transition receptor; MMP-9, matrix metalloproteinase 9; PI3K, phosphatidylinositol 3-kinase; PDGF, platelet-derived growth factor; PKC, protein kinase C; RGC, response gene to complement; ROS/RNS, reactive oxygen species/reactive nitrogen species; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.

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    Molecular Cancer Research: 8 (11)
    November 2010
    Volume 8, Issue 11
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    Cancer and the Complement Cascade
    Martin J. Rutkowski, Michael E. Sughrue, Ari J. Kane, Steven A. Mills and Andrew T. Parsa
    Mol Cancer Res November 1 2010 (8) (11) 1453-1465; DOI: 10.1158/1541-7786.MCR-10-0225

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    Cancer and the Complement Cascade
    Martin J. Rutkowski, Michael E. Sughrue, Ari J. Kane, Steven A. Mills and Andrew T. Parsa
    Mol Cancer Res November 1 2010 (8) (11) 1453-1465; DOI: 10.1158/1541-7786.MCR-10-0225
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    • Article
      • Abstract
      • Introduction
      • Complement Promotes Oncogenesis
      • Complement Sustains Tumorigenesis
      • Complement Prevents Cell Death
      • Complement Promotes Angiogenesis
      • Complement Promotes Cellular Invasion and Migration
      • Complement and Immunosurveillance
      • Conclusion
      • Disclosure of Potential Conflicts of Interest
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