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

Abstract

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.

Monomeric CRP Aggravates Myocardial Injury After Myocardial Infarction by Polarizing the Macrophage to Pro-Inflammatory Phenotype Through JNK Signaling Pathway

“…The importance of this finding is highlighted by the findings that mCRP was involved in the pathological process after acute myocardial infarction. 14,31 We and other studies further illustrated that increased localization of mCRP was observed in ischemic stroke or the infarcted myocardium after myocardial infarction. 18,32,33 Here, we further demonstrated that mCRP increased and prolonged the duration of proinflammatory cells in infarcted myocardium after MI through the JNK pathway.…”

“…Monomeric CRP (mCRP) can be dissociated from its pentamer (pCRP) after binding to activated platelets, apoptotic/necrotic cells, or microparticles (MPs). 13,14 However, it has distinct antigenicity-expressing neoepitopes differing from pCRP. This conformation rearrangement results in significant changes different from the biological activities of CRP.…”

“…15,17,18 Monomeric CRP induces endothelial dysfunction, which also induces pro-inflammatory cytokine release from human monocytes. 14,16 However, there are few data examining the direct effect and its possible signal pathways of mCRP on macrophage phenotype polarization and its pathophysiological functions after acute myocardial infarction. In the present study, we examined the hypothesis that mCRP may play a pro-inflammatory role on macrophage polarization and therefore impair the repair of the infarct myocardial after acute myocardial infarction.…”

CRP Serum Levels Are Associated with High Cardiometabolic Risk and Clinical Disease Activity in Systemic Lupus Erythematosus Patients

“…In other pathologies such as cancer, the roles of pCRP and mCRP have also been described [ 49 ]. However, neither study conducted on SLE patients have reported the role of CRP according to its structure.…”

The Predictive Potential of the Baseline C-Reactive Protein Levels for the Efficiency of Immune Checkpoint Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

“…CRP can also foster the formation of the tumor microenvironment (TME) ( 60 , 61 ), which might impair the effect of ICIs. What is more, CRP is an indicator of body damage ( 62 ). It means that, compared with patients with low pretreatment CRP level, patients with high pretreatment CRP level perhaps have worse health and cancer circumstances, which will also affect the effectiveness of ICIs.…”