|Year : 2015 | Volume
| Issue : 4 | Page : 565-568
C-reactive protein: An inflammatory biomarker in oral cancer
Ashwini Kumar Mengji, Uday Shankar Yaga, Radhika Besta, Swetha Soankamble
Department of Oral Medicine and Radiology, MNR Dental College and Hospital, Sangareddy, Telangana, India
|Date of Submission||21-Oct-2015|
|Date of Acceptance||19-Jun-2016|
|Date of Web Publication||19-Aug-2016|
Dr. Swetha Soankamble
Department of Oral Medicine and Radiology, MNR Dental College and Hospital, Narsapur Road, Sangareddy 502 294, Telangana
Source of Support: None, Conflict of Interest: None
| Abstract|| |
C-reactive protein (CRP) is a plasma phase protein that takes part in systemic responses to inflammatory reactions. Its serum concentration can increase up to 1000 folds or more in relation to acute stimuli due to infections, tissue injuries, and malignant disorders. It is highly resistant to proteolysis, principally synthesized in the liver in response to proinflammatory cytokines, i.e. interleukin (IL)-6, IL-1β, and tumor necrosis factor. These cytokines are seen to be related to neoplastic disorders. It forms an integral component of innate immunity and serves primarily to recognize potential pathogens and damaged cells. The present article summarizes the importance of CRP and its significance in oral cancer and associated disorders. It was found that a lowered CRP level may prove to be beneficial in prevention and treatment of oral cavity cancer.
Keywords: Cytokine, inflammation, pentraxin, prognostic, CRP
|How to cite this article:|
Mengji AK, Yaga US, Besta R, Soankamble S. C-reactive protein: An inflammatory biomarker in oral cancer. J Indian Acad Oral Med Radiol 2015;27:565-8
|How to cite this URL:|
Mengji AK, Yaga US, Besta R, Soankamble S. C-reactive protein: An inflammatory biomarker in oral cancer. J Indian Acad Oral Med Radiol [serial online] 2015 [cited 2022 Aug 16];27:565-8. Available from: https://www.jiaomr.in/text.asp?2015/27/4/565/188762
| Introduction|| |
Acute phase proteins are a large group of plasma proteins released into blood when triggered by acute inflammatory reactions in physiological and pathological conditions followed by injury, trauma, stress, and malignant disorders.  Positive acute phase proteins (PAPPs) and negative acute phase proteins (NAPPs) are those whose plasma levels increase and decrease, respectively, by at least 25% in response to inflammatory disorders.  They have well-recognized approach in human medicine and have described its usefulness in the diagnosis and prognosis of various inflammatory and organ diseases, and also in cancer treatment.  The most indicative PAPPs are C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), haptoglobin, fibrinogen, ceruloplasmin, and serum amyloid A, whereas NAPPs include albumin, thyroxin binding protein, transthyretin, and insulin-like growth factor 1. 
CRP is an acute phase protein, the levels of which alter on daily basis, increases with aging, increased blood pressure, smoking, coffee and alcohol consumption, decreased physical activity, raised levels of triglycerides, insulin resistance and diabetes, high-protein diet, chronic tiredness and suffering from sleep disturbances, and depression.  CRP belongs to pentraxins protein family; pentraxins are the ancient proteins having cyclic pentameric arrangement of five noncovalently bound identical subunits  placed in a symmetric cyclic design around a central pore, determining a pentameric, discoid, and flattened configuration.  One of the oldest historic members of the pentraxin family is CRP of an arachnid, Limulus polyphemus, the horseshoe crab which has hexameric configuration rather than pentameric configuration,  and which shares 25% amino acid sequence with its mammalian equivalents and 71% sequence is shared by mouse CRP and human CRP. 
| History|| |
CRP was discovered by William Tillet and Thomas Frances in 1930  in Oswald Avery's laboratory during their work on patients suffering from Streptococcus pneumoniae infection.  They found that patients' serum CRP has the capacity to ligate with the C-polysaccharide element of the pneumococcal cell wall; hence, its named as "C-reactive protein."  It was even reported by these investigators in the serum of patients with acute bacterial endocarditis, acute rheumatic fever and staphylococcal osteomyelitis.  After 40 years, Volanakis and Kaplan identified phosphocholine (PCh) (first defined ligand of CRP) as a specific ligand for CRP in the pneumococcal C polysaccharide. Since then, several other ligands have been identified. 
| Structure|| |
CRP is an indicator of the acute phase of inflammation with pentameric nonglycosylated polypeptide subunits with each component composed of 206 amino acid residues.  The gene for CRP coding is present on the 1 st chromosome; it has only one intron that separates the region encoding signal peptide from the region encoding the mature peptide.  It consists of ﬁve noncovalently bound similar subunits and has calcium-dependent binding speciﬁcity for PCh.  PCh is present in phospholipid layer of cell membranes and plasma lipoproteins and in complex polysaccharides of plants, fungi and bacteria, and also seen to bind specifically with small nuclear ribonucleoprotein particles.  The human CRP was crystallized in 1947  and showed cyclic 5-fold symmetric aggregation of protomers, each having a ﬂattened jellyroll appearance, arranged into two layers of β-sheets.  Two calcium ions are bound 4 Angstrom apart by protein side chains coming from loops collected at the concave side which is the site of ligand binding. The other side carries a single α-helix. The pentameric disc exhibits five helices on one side and ten calcium ions on the other.  The calcium atoms are necessary for all physiological ligand binding by CRP and also stable both the structure of the protomer and the integrity of the natural pentamer [Figure 1]. 
|Figure 1: Illustration showing the structure of C - Reactive protein representing the pentameric polypeptide subunits with 2 calcium binding sites and 1 binding site for phosphocholine|
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| Synthesis|| |
The synthesis of CRP occurs in the hepatocytes and is regulated by proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor, which are also observed in different malignancies. Newly synthesized CRP is rapidly secreted by liver cells and therefore difficult to reveal within the cytoplasm [Figure 2].  De novo hepatic synthesis starts rapidly after a single stimulus with a half-life of about 19 h. The levels increase within 6-8 h with a peak reaching at 24-48 h. Liver is the principal site of CRP production, but there are other extrahepatic sites where its mRNA is identified, like the epithelial cells of respiratory tract, T-lymphocytes,  adipose tissues, epithelial cells of renal cortical tubules, and atherosclerotic plaques in smooth muscle cells and macrophages. 
|Figure 2: Illustration showing synthesis of C - Reactive protein. During acute and chronic inflammation pro - inflammatory cytokines are released which acts on liver to produce C-Reactive protein|
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There are two hypotheses that are related with elevated CRP levels as a sign of chronic inflammation. The induction hypothesis postulated by Rudolf Virchow in 1863 that the origin of cancer was at site of chronic inflammation results in cell proliferation beyond limits and results in stimulation of cascade of cellular actions leads to induction of unaltered DNA damage. Next, the response hypothesis that stated that the immune response of the host as a consequence of tumor growth could be the reason for the elevation in CRP levels.  CRP levels are measured using latex slide agglutination or immune-turbidimetric or immune-electrophoretic assays. The high-sensitivity CRP assay uses labeled polyclonal or monoclonal anti-CRP antibodies in an immunofluorescent assay or enzyme-linked immunosorbent assay. 
| Physiological Functions|| |
There are many disputes about the normal functions of human CRP as there is neither deficiency nor structural polymorphism yet reported, but it is suggested that it has a beneficial role and is related to both innate immunity against infections and suitable protective handling and disposal of damaged autologous cells and lipids.  The rise and fall of CRP in response to inflammatory reaction make it a highly sensitive indicator of inflammation than ESR and white blood cell count.  CRP binds to specific macrophage receptors for IgG resulting in opsonization of bacteria.  Opsonization involves covering of the bacterial surface as it can be recognized by cells of the immune system, usually macrophages and neutrophils. Therefore, opsonization by CRP encourages the uptake and removal of these cells by phagocytes. CRP also can interact with natural killer cells and monocytes and may increase tumoricidal activity.  It modulates macrophage function as macrophages possess CRP receptors, and therefore, it potentiates or upregulates the proinflammatory cytokine synthesis such as IL-1α, IL-1β and tumor necrosis factor-alpha; thus, CRP plays a dual pro and anti-inflammatory part in the regulation of the complement system. 
| Role of C-reactive Protein in Oral Cancer|| |
The association between cancer and inﬂammation has been researched over 100 years. In 1863, Rudolf Virchow was the ﬁrst to document the "lymphoreticular inﬁltrate" in neoplastic tissue and hypothesized that the origin of cancer was at the location of chronic inﬂammation.  Oral cancer is one of the most common cancers with a survival rate of 5 years. Almost 90% of the oral cancers are squamous cell carcinomas, which have shown its origin from potentially malignant disorders such as erythroplakia, erythroleukoplakia, leukoplakia, oral submucous fibrosis, and oral lichen planus.  The prognostic value of serum CRP has been already described in primary malignancies, such as esophageal, esophagogastric, colorectal, hepatocellular, urinary bladder, ovarian and cervical cancers, melanoma, and thymoma, and in advanced stage of cancers such as inoperable nonsmall cell pulmonary cancer, nonresectable pancreatic cancer, biliary tract cancer and metastatic brain diseases. Elevated CRP has been related with the worse survival rate for patients with the advancement of these malignant disorders. 
A study by Faraz et al. conducted in patients with oral squamous cell carcinoma (OSCC) showing increased serum CRP levels before the start of treatment presented the worst prognosis, and nearly all of the patients died within 5 years, whereas the others with normal CRP had survived even after 5 years of surgical resection. Therefore, it was concluded that higher levels of preoperative CRP are prognostic biomarkers in patients with OSCC.  A study by Sunil et al. correlated that the clinical and pathological factors such as tumor size, lymph node metastasis, tumor staging, and survival rate with serum CRP levels in patients with OSCC were treated with primary surgery and microvascular free flap reconstruction. They had undergone postradiation therapy depending on histopathological need. The study suggested that the raised levels of CRP can be used as an independent prognostic factor and associated with worse overall survival rate. 
Research done on proinflammatory cytokines and CRP in oral cavity cancer patients determined the relationship between the serum levels of acute phase markers and the results confronted with squamous cell carcinoma antigen. The results showed increased levels during the acute phase of malignancy and interpreted that they can be used as additional biomarkers and responsible for local recurrence rate after nonradical surgery in head and neck cancer.  Prior studies have suggested the role of CRP as a prognostic indicator in advanced cancer patients. A study compared the advanced cancer patients to normal persons with loss of weight and anorexia and concluded the CRP may be an important value in prognostic inflammatory and nutritional index, whereas other studies compared elevated serum Vitamin B12 and CRP and found that these factors were independent and essential prognostic marker for mortality in terminally ill cancer patients. 
The other associated diseases include potentially malignant disorders. They include oral leukoplakia, erythroleukoplakia, erythroplakia, oral submucous fibrosis and squamous papilloma having a high-risk to progress toward malignant transformation.  A study by Anand and Sumit conducted on potentially malignant disorders with elevated serum CRP levels displayed highly significant differences with different grades of dysplasia and concluded that high preoperative CRP levels are extremely associated with the development of oral cancer. 
| Conclusion|| |
Several tumor markers have been studied to forecast the physiological and biological behavior and prognosis in oral cancer but are not obtainable in day-to-day practice due to nonavailability, time consumption and high laboratory cost. Therefore, a simple biomarker such as serum CRP can be useful as various studies have shown the presence of an elevated serum CRP level as an independent prognostic indicator and can be used as a biomarker in oral cancer. Determining CRP levels pre- and post-operatively would be relevant and useful to oral surgeons because CRP measurement is rapid, cost effective and easily performed. Overall, the current studies suggest an association between CRP and oral cancer with potential implications for future treatment progressions.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
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