Fueling the flames of colon cancer – does CRP play a direct pro-inflammatory role?

Abstract

BackgroundSystemic inflammation, diagnostically ascribed by measuring serum levels of the acute phase reactant C-reactive protein (CRP), has consistently been correlated with poor outcomes across cancer types. CRP exists in two structurally and functionally distinct isoforms, circulating pentameric CRP (pCRP) and the highly pro-inflammatory monomeric isoform (mCRP). The aim of this pilot study was to map the pattern of mCRP distribution in a previously immunologically well-defined colon cancer (CC) cohort and explore possible functional roles of mCRP within the tumor microenvironment (TME).MethodsFormalin-fixed, paraffin-embedded (FFPE) tissue samples from 43 stage II and III CC patients, including 20 patients with serum CRP 0-1 mg/L and 23 patients with serum CRP >30 mg/L were immunohistochemically (IHC) stained with a conformation-specific mCRP antibody and selected immune and stromal markers. A digital analysis algorithm was developed for evaluating mCRP distribution within the primary tumors and adjacent normal colon mucosa.ResultsmCRP was abundantly present within tumors from patients with high serum CRP (>30 mg/L) diagnostically interpreted as being systemically inflamed, whereas patients with CRP 0-1 mg/L exhibited only modest mCRP positivity (median mCRP per area 5.07‰ (95%CI:1.32-6.85) vs. 0.02‰ (95%CI:0.01-0.04), p<0.001). Similarly, tissue-expressed mCRP correlated strongly with circulating pCRP (Spearman correlation 0.81, p<0.001). Importantly, mCRP was detected exclusively within tumors, whereas adjacent normal colon mucosa showed no mCRP expression. Double IHC staining revealed colocalization of mCRP with endothelial cells and neutrophils. Intriguingly, some tumor cells also colocalized with mCRP, suggesting a direct interaction or mCRP expression by the tumor itself.ConclusionOur data show that the pro-inflammatory mCRP isoform is expressed in the TME of CC, primarily in patients with high systemic pCRP values. This strengthens the hypothesis that CRP might not only be an inflammatory marker but also an active mediator within tumors.

Monomeric C-Reactive Protein Potential Utilization in the Histological Assessment of Inflammatory Bowel Disease (IBD) Patients

“…Additionally, mCRP expression was significantly associated with tumor-infiltrating neutrophils, similar in that respect, to our study. The macrophages distributed in tumoral areas showed less mCRP positivity, compared with our results, suggesting that mCRP might just be an amplifier of the local inflammatory response in this case [20]. We consider that a correlation between the consistent data offered by this study with an extension of our study to a larger cohort of IBD patients could provide a novel mechanistic understanding of the risk of developing IBD-related neoplasia in patients with UC and CD.…”

“…In cardiovascular and neurovascular diseases and in the tumoral pathology of the colon, mCRP was stained in endothelial cells, supporting the hypothesis that these cells are targeted for the dissociation of pCRP into mCRP, with perhaps a critical contribution to the localization of the inflammatory response [ 20 - 25 ]. In our study, and in contrast, mCRP was expressed only in intravascular inflammatory cells, without association with vascular endothelium suggesting at least partially a nonsystemic source and likely in situ precipitation.…”

“…Although the role of mCRP in IBD progression and development of extraintestinal complications was hypothesized within the literature [ 19 ], the identification of these molecules at the level of intestinal mucosa has not been examined in patients with UC and CD. Regarding the digestive system, there is a single study published by Kostner et al that recently identified mCRP molecules in the tumoral areas of the colon [ 20 ]. Using artificial intelligence-based algorithms, the pattern of mCRP distribution was analyzed, and it was reported that the monomer was present exclusively within the tumor area, whereas adjacent normal colon mucosa showed no mCRP staining and that the level of expression strongly correlated with the level of circulating pentameric CRP (pCRP).…”

C-Reactive Protein in Atherosclerosis—More than a Biomarker, but not Just a Culprit

“…Moreover, in vitro experiments have shown that mCRP decreases the uptake of acetylated LDL by human umbilical vein endothelial cells (HUVECs) [ 76 ]. Nevertheless, some of the studies that investigated the effects of CRP on LDL uptake and foam cell formation did not distinguish between the different isoforms of CRP, even though the bioactivity of CRP is known to depend on its structural status [ 7 , 8 , 9 ]. A few studies have purposely distinguished between the pCRP and mCRP isoforms, but these have also reported somewhat controversial findings [ 60 , 65 , 76 ].…”

“…This is formed at local inflammation sites as a consequence of pCRP dissociation. In contrast to pCRP, mCRP is mostly tissue bound and has significantly lower aqueous solubility [ 8 , 9 ]. There are also structures consisting of partially dissociated pCRP existing as membrane-bound intermediates (described as mCRP m or pCRP*), which act similar to mCRP.…”