Enhancement of Human Cancer Cell Motility and Invasiveness by Anaphylatoxin C5a via Aberrantly Expressed C5a Receptor (CD88)

Nitta, Hidetoshi; Wada, Yasuhiko; Kawano, Yoshiaki; Murakami, Yoji; Irie, Atsushi; Taniguchi, Keisuke; Kikuchi, Ken; Yamada, Gen; Suzuki, Kentaro; Honda, Jiro; Wilson-Morifuji, Masayo; Araki, Nobuhito; Eto, Masatoshi; Baba, Hideo; Imamura, Takahisa

doi:10.1158/1078-0432.ccr-12-1204

Cited by 76 publications

(87 citation statements)

References 39 publications

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“…Aggressive type UCC cells expressed C5aR at the greatest rate (73%) ( Fig. 1; Table I) compared with the C5aR-positive rates of other types of cancer, as previously reported (22). This finding may indicate an association between C5aR expression and UCC aggressiveness.…”

Section: Discussionsupporting

confidence: 84%

“…This finding may indicate an association between C5aR expression and UCC aggressiveness. Invasiveness of C5aR-expressing cancer cells is augmented by C5a (22), which is present in the cancer microenvironment (17)(18)(19)(20). UCC cells at the invasive front are in direct contact with interstitial fluid that contains C5, which facilitates C5a release by cancer cell proteases (23).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the poor outcomes of patients with C5aR-positive UCC ( Fig. 2; Table II) may be associated with the invasive potential of C5a-activated C5aR-positive cancer cells (22).…”

Section: Discussionmentioning

confidence: 99%

“…Although it has not yet been demonstrated in human UCC, C5aR signaling suppresses apoptosis, induces T-cell expansion via the enhanced expression of Bcl-2 (32) and enhances neuronal cell survival via inhibition of caspase-3 activation (33). C5a is present in the cancer microenvironment (17,20,23), where, by stimulation with C5a, the apoptosis of C5aR-expressing UCC may be suppressed; this supression facilitates the growth and development of cancer in concert with the C5a-elicited enhancement of proliferation (24) and invasiveness (22). Thus, C5aR expression in UCC may correlate with the low survival rate exhibited by patients (Table II).…”

Section: Discussionmentioning

confidence: 99%

“…C5a functions by binding to the C5a receptor (C5aR), which was originally identified in leukocyte cell lines (21). In our previous study, aberrant C5aR expression in cancer cells was identified in a number of different organs and C5a was demonstrated to enhance cancer cell invasiveness by activating motility and increasing matrix metalloproteinase release in a C5aR-dependent manner (22). Furthermore, direct C5a release from C5 by cell membrane proteases of cancer cells and promotion of C5aR-expressing cancer cell invasiveness by C5a was demonstrated, indicating that a self-activation circuit via C5aR exists in cancer cells that express C5aR and proteases on the cell surface (23).…”

Section: Introductionmentioning

confidence: 99%

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C5a receptor expression is associated with poor prognosis in urothelial cell carcinoma patients treated with radical cystectomy or nephroureterectomy

et al. 2016

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Abstract.Patients with aggressive urothelial cell carcinoma (UCC) that undergo radical cystectomy or nephroureterectomy exhibit markedly high rates of disease recurrence and mortality. To select appropriate adjuvant thxerapies in addition to radical surgery, the identification of predictive prognostic markers for UCC patients is required. The aim of the present study was to identify such markers, by evaluating the association of UCC complement component 5 (C5) fragment a (C5a) receptor (C5aR) expression, detected using immunohistochemistry, with clinicopathological parameters and survival outcomes of UCC patients. The results revealed that C5aR was expressed in cancer cells, particularly at the invasive front, but not in noncancerous urothelial cells or adjacent cells. The UCC C5aR-positive rate of patients treated with radical surgeries was 73% (38/52) and the rate was 83% (20/24) at stages I-II of disease. No correlation between C5aR expression and any of clinicopathological parameters, which included gender, tumor location, World Health Organization grade, T stage, vessel invasion and stage of disease, was identified. However, univariate and multivariate analyses revealed that C5aR-positive UCC patients exhibited significantly lower overall survival rates [hazard ratio (HR), 3.14; 95% confidence interval (CI), 1.03-9.60; P=0.035 and HR, 3.92; 95% CI, 1.15-13.4; P=0.029, respectively] and 5-year survival rates (0.42 vs. 0.83) compared with C5aR-negative UCC patients. Furthermore, 5-year survival and disease-specific survival rates were lower in patients with C5aR-positive UCC (0.51; 95% CI, 0.30-0.71) than patients with C5aR-negative UCC (0.83; 95% CI, 0.62-1.00). These results indicate that UCC C5aR expression is predictive of poor patient outcomes and thus may lead to the appropriate selection of adjuvant therapies at earlier UCC stages, which could improve patient prognosis. IntroductionUrothelial cell carcinoma (UCC) is one of the most common types of cancer in the USA, accounting for ~4.5% of all newly diagnosed cancer cases and 2.8% of all cancer-associated mortalities in 2013 (1). In the USA, the most common site of UCC is the bladder, and bladder UCC is the fourth most common type of cancer and the sixth leading cause of cancer-associated mortality in males (1). Bladder UCC may be classified into two subtypes at diagnosis, non-muscle and muscle-invasive, which exhibit distinct clinical features (2). The non-muscle-invasive subtype commonly recurs in the bladder cavity and accounts for 70-80% of cases of bladder UCC, with muscle invasion present in only 10-20% of cases. The 5-year survival rate of the non-muscle-invasive subtype of UCC is >90%. By contrast, muscle-invasive bladder UCC, which accounts for ~20% of bladder UCC cases, exhibits a poor prognosis with a 5-year survival rate of <50%. Carcinoma in situ (CIS), which is classified into the non-muscle invasive aggressive subtype, is localized to the epithelium and exhibits invasive and metastatic potential. In patients with aggressive bladder UCC (...

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

“…Thus, the poor outcomes of patients with C5aR-positive UCC ( Fig. 2; Table II) may be associated with the invasive potential of C5a-activated C5aR-positive cancer cells (22).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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C5a receptor expression is associated with poor prognosis in urothelial cell carcinoma patients treated with radical cystectomy or nephroureterectomy

et al. 2016

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Complement anaphylatoxins as immune regulators in cancer

2014

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The role of the complement system in innate immunity is well characterized. However, a recent body of research implicates the complement anaphylatoxins C3a and C5a as insidious propagators of tumor growth and progression. It is now recognized that certain tumors elaborate C3a and C5a and that complement, as a mediator of chronic inflammation and regulator of immune function, may in fact foster rather than defend against tumor growth. A putative mechanism for this function is complement-mediated suppression of immune effector cells responsible for immunosurveillance within the tumor microenvironment. This paradigm accords with models of immune dysregulation, such as autoimmunity and infectious disease, which have defined a pathophysiological role for abnormal complement signaling. Several types of immune cells express the cognate receptors for the complement anaphylatoxins, C3aR and C5aR, and demonstrate functional modulation in response to complement stimulation. In turn, impairment of antitumor immunity has been intimately tied to tumor progression in animal models of cancer. In this article, the literature was systematically reviewed to identify studies that have characterized the effects of the complement anaphylatoxins on the composition and function of immune cells within the tumor microenvironment. The search identified six studies based upon models of lymphoma and ovarian, cervical, lung, breast, and mammary cancer, which collectively support the paradigm of complement as an immune regulator in the tumor microenvironment.

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Prostate cancer C5a receptor expression and augmentation of cancer cell proliferation, invasion, and PD‐L1 expression by C5a

et al. 2020

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BackgroundThe treatment of castration‐resistant prostate cancer (CRPC) is a urological issue. Recent studies have revealed cancer promotion via the C5a–C5a receptor (C5aR) system. To establish a new therapeutic target for CRPC, we investigated an association of the system with CRPC progression and evasion from the antitumor immune responses.MethodsC5aR and PD‐L1 were immunostained in the prostate cancer (PC) tissues. The relationship of PC C5aR expression to clinicopathological parameters was analyzed. CRPC cell lines were examined for C5aR expression by real‐time reverse transcription polymerase chain reaction, immunoblotting, and flow cytometry. C5a effects were examined on CRPC cell glutamine consumption, proliferation, invasion, and PD‐L1 expression.ResultsPC cells expressed C5aR in 83 of the 161 patients (52%) and in three of the six CRPC patients. Basal cells, but not luminal cells, of noncancerous prostate glands expressed C5aR. Three CRPC cell lines expressed C5aR. C5a increased CRPC cell glutamine consumption 2.1‐fold, proliferation 1.3–1.6‐fold, and invasion 2–3‐fold in a C5a‐concentration and a C5aR‐dependent manner. High expression of C5aR did not relate to the PC patients' clinical parameters but the PD‐L1‐positive rate was higher in the C5aR high‐expression patients (37.5%) compared to low‐ or no expression patients (17.8%), and double‐positive PC cells were present. C5a increased CRPC cell PD‐L1 production 1.4‐fold and cell‐surface expression 2.6‐fold.ConclusionsC5aR expression of PC cells in patients' tissues and C5a augmentation of C5aR‐dependent CRPC proliferation, invasion, and PD‐L1 expression suggested participation of the C5a–C5aR system in CRPC promotion and evasion from antitumor immune responses. Targeting this signaling pathway may provide a useful therapeutic option for CRPC.

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Enhancement of Human Cancer Cell Motility and Invasiveness by Anaphylatoxin C5a via Aberrantly Expressed C5a Receptor (CD88)

Cited by 76 publications

References 39 publications

C5a receptor expression is associated with poor prognosis in urothelial cell carcinoma patients treated with radical cystectomy or nephroureterectomy

C5a receptor expression is associated with poor prognosis in urothelial cell carcinoma patients treated with radical cystectomy or nephroureterectomy

Complement anaphylatoxins as immune regulators in cancer

Prostate cancer C5a receptor expression and augmentation of cancer cell proliferation, invasion, and PD‐L1 expression by C5a

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