DataSheet_1_C-Reactive Protein and Cancer: Interpreting the Differential Bioactivities of Its Pentameric and Monomeric, Modified Isoforms.docx

C-reactive protein (CRP) was first recognized in the 1940s as a protein that appeared in blood during acute episodes of infectious disease. Its presence and pharmacodynamics were found in essentially all diseases that involved tissue damage and inflammation. Identified as a major component of the innate, unlearned immunity, it became a useful diagnostic marker for the extent of inflammation during disease exacerbation or remission. Efforts to define its true biological role has eluded clear definition for over a half-century. Herein, a unifying concept is presented that explains both pro-inflammatory and anti-inflammatory activities of CRP. This concept involves the recognition and understanding that CRP can be induced to undergo a pronounced, non-proteolytic reorganization of its higher-level protein structures into conformationally distinct isomers with distinctive functional activities. This process occurs when the non-covalently associated globular subunits of the pentameric isoform (“pCRP”) are induced to dissociate into a monomeric isoform (“mCRP”). mCRP consistently and potently provides pro-inflammatory activation and amplification activities. pCRP provides weak anti-inflammatory activities consistent with low-level chronic inflammation. mCRP can spontaneously form in purified pCRP reagents in ways that are not immediately recognized during purification and certification analyses. By now understanding the factors that influence pCRP dissociate into mCRP, many published reports investigating CRP as a biological response modifier of host defense can be reevaluated to include a discussion of how each CRP isoform may have affected the generated results. Specific attention is given to in vitro and in vivo studies of CRP as an anti-cancer agent.

C反应蛋白（C-reactive protein, CRP）最早于20世纪40年代被发现，是一类在急性感染性疾病发作时释放入血的蛋白质。后续研究证实，几乎所有涉及组织损伤与炎症的疾病中均存在该蛋白及其药效动力学特征。它被认定为先天固有免疫（innate, unlearned immunity）的核心组成成分，现已成为评估疾病加重或缓解阶段炎症程度的实用诊断标志物。半个多世纪以来，学界始终未能明确界定其真正的生物学功能。本文提出了一个统一的理论框架，可同时解释CRP的促炎与抗炎双重活性。该理论基于以下认知：CRP可被诱导发生显著的非蛋白水解高级结构重排，进而形成构象迥异、功能特性独特的异构体。当五聚体异构体（pentameric isoform, pCRP）的非共价结合球状亚基解离为单体异构体（monomeric isoform, mCRP）时，便会触发这一重排过程。mCRP可持续且高效地发挥促炎激活与放大活性；而pCRP仅表现出较弱的抗炎活性，这与低度慢性炎症的状态相符。纯化的pCRP制剂中可自发形成mCRP，且该过程在纯化与质量认证分析阶段往往难以被及时识别。如今，通过明确影响pCRP解离为mCRP的各类因素，诸多将CRP作为宿主防御生物应答调节剂的已发表研究可被重新评估，进而探讨两种CRP异构体对实验结果的潜在影响。本文还特别关注了CRP作为抗癌剂的体外与体内研究。