Complement activation in astrocytomas: deposition of C4d and patient outcome

Abstract

BackgroundC4d is a cleavage product of complement component C4 and is considered to serve as a marker for the site of complement activation. In this study C4d staining of grade I-IV astrocytic tumors was studied to explore if there is an association between complement activation and the grade of tumor, or patient survival.MethodsTissue micro-array samples of 102 astrocytomas were stained immunohistochemically. The material consisted of 9 pilocytic astrocytomas and 93 grade II-IV astrocytomas, of which 67 were primary resections and 26 recurrent tumors. The intensity of C4d staining as well as extent of C4d and CD34 staining were evaluated. The intensity of C4d staining was scored semiquantitatively. The extent of the staining was counted morphometrically with a point counting grid yielding a percent of C4d and CD34 positive area of the sample.ResultsThe intensity and extent of C4d staining increased in grade II-IV diffusely infiltrating astrocytoma tumors in line with the malignancy grade (p = 0.034 and p = 0.016, respectively, Kruskal-Wallis test). However, C4d positive tumor area percentages were higher in grade I pilocytic astrocytomas than in grade II-IV diffusely infiltrating astrocytomas (p = 0.041, Mann–Whitney test). There was a significant correlation between CD34 positive and C4d positive endothelial area fraction in diffusely infiltrating astrocytomas (p < 0.001, Pearson correlation). In these tumors, the increasing intensity of C4d staining was also associated with worsened patient outcome (p = 0.014, log-rank test).ConclusionThe worsening of patient outcome and malignant progression of tumor cells seem to be connected to microenvironmental changes evoked by chronically activated complement.

C5a receptors C5aR1 and C5aR2 mediate opposing pathologies in a mouse model of melanoma

“…In line with previous reports for other cancers (4, 5), we provide evidence that complement is activated in human melanoma tissue. Although there is no survival data available for the melanoma tissue arrays analyzed in the present study, levels of circulating or tissue C4d have been reported to predict outcomes in patients with primary nonsmall lung cancer (5), malignant pleural mesothelioma (41), and astrocytoma (42). Similar to previous reports showing C4d deposition mainly associated with tumor cells and the extracellular matrix surrounding them (5,42), we showed diffuse staining in areas of tumor tissue.…”

Circulating complement component 4d (C4d) correlates with tumor volume, chemotherapeutic response and survival in patients with malignant pleural mesothelioma

“…One complement-related protein is the degradation protein C4d, a stable cleavage product of C4, accumulating following classical and lectin pathway activation 12 – 14 . C4d deposition in a tissue is regarded as an indirect proof of an activation of the complement cascade 13 . C4d is usually bound stably to the target structure but may eventually enter the circulation.…”

“…C4d is usually bound stably to the target structure but may eventually enter the circulation. Of note, C4d is routinely used as a tissue biomarker to investigate allograft tissue rejections in kidney transplants 13 – 15 . C4d has already been found to have a prognostic role in different types of cancer 12 , 13 , 16 .…”

Tumour exosomes display differential mechanical and complement activation properties dependent on malignant state: implications in endothelial leakiness

“…Recent work links chronic intratumoural complement activation to tumour progression. For instance, the measurement of C4d levels in astrocytomas correlated with cancer severity grade ( 16 ). Another study in immunocompetent mice bearing a syngeneic tumour has strongly indicated that intratumoural accumulation of complement activating nanoparticles can accelerate tumour growth through C5a generation ( 17 ).…”