Mini Review

Evaluation of the Relationship between C-Reactive Protein and Prostate Cancer

Hashimoto N*
Graduate School of Life and Environmental Sciences, Kindai University School of Medicine, Japan


*Corresponding author: Naoki Hashimoto, Graduate School of Life and Environmental Sciences, Kindai University School of Medicine, 377-2 Ohno-Higashi Osaka-Sayama, Osaka 589-8511, Japan


Published: 30 May, 2016
Cite this article as: Hashimoto N. Evaluation of the Relationship between C-Reactive Protein and Prostate Cancer. Clin Oncol. 2016; 1: 1005.

Abstract

In the last decade, accumulating evidence has supported Virchow's hypothesis that cancer and inflammation are linked. Many investigators have demonstrated that the presence of a systemic inflammatory response, as evidenced by an elevated C-reactive protein (CRP) level or elevated interleukin-6 (IL-6) levels, are associated with a poor outcome in patients with many types of cancer, including prostate cancer. CRP is a serum acute phase reactant and a well established inflammatory marker. CRP secretion by hepatocytes appears controlled by IL-6. We examined the role of CRP to predict treatment response and tumor recurrence. Thumer et al. have indicated that elevated CRP levels and poor prognosis was independent of other measures of prognosis such as tumor stage, Gleason grading and PSA level at diagnosis. CRP had a specific role in prostate cancer progression and or resistance. Therefore, inhibitors of CRP (Siltuximab) might make for attractive therapeutic agents.

Keywords: CRP (C-reactive protein); IL6; Prostate cancer; Prostate-specific Antigen (PSA)

Introduction

Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of death in men [1]. More accurate and predictive markers should be applied for PCa. Recently, the presence of a systemic inflammatory response, which is measured by an acute-phase reactant has been identified to be associated with a poor prognosis in various types of cancers such as lung cancer, gastric cancer, colorectal cancer, renal cell carcinoma and others [2].
The use of biological tumor markers to help prognosis has appeal. An ideal potential tumor marker should have a long half-life, be measured accurately and precisely by a simple and inexpensive blood test. It is also important that it be sensitive to change so that it can be followed over time through serial measurements. A few biologic marker meet these criteria [3], C-reactive protein (CRP) is one.

CRP

CRP is an acute phase reactant, which reflects tissue injury [4]. The half-life is 19 hours in both health and disease. CRP is a surrogate for interleukin 6 (IL6) action [5]. IL-6 acts on hepatocytes to increase the synthesis of CRP. Interleukin-1 (IL-1) and tumor necrosis factor (TNF) also stimulate CRP synthesis [6]. CRP is a non-specific but fairly sensitive marker of acute-phase inflammation. Major elevation of CRP levels are bacterial infection, inflammatory diseases, cancer, tissue necrosis and trauma. A strong positive correlation between high CRP and high IL-6 levels was shown in advanced pancreatic cancer [7]. Elevated CRP levels have been linked to shorter survival in several cancers [8]. While some studies reported that in PCa patients with a higher CRP level was significantly associated with poor prognosis in PCa [9]. But other studies did not show any significant relationship between CRP and survival in PCa patients [10]. In this paper, we described the review of the relationship between elevated CRP and prostate cancer.

Prostate-specific Antigen Levels (PSA)

PSA is produced exclusively by epithelial cells of prostate gland. Disruption of the cell to cell architecture of prostate epithelium results in increased serum PSA levels [11]. Apart from prostate cancer, nonmalignant condition and prostate manipulation such as benign prostate hyperplasia (BPH), acute/chronic prostatitis elevate serum PSA levels [12]. PSA levels alone are not a reliable parameter between prostate cancer and benign conditions of the prostate. A variety of parameters have been identified and applied for prostate cancer. But PSA is most popular parameter for the diagnosis of prostate cancer. Other parameters are used to diagnosis of prostate cancer. Epithelial growth factor receptor, pAKT nuclear factor-kappa B, macrophage inhibitory cytokine-1, matrix metalloproteinase-1 and matrix metalloproteinase-9 were used for the prediction of the prognosis of prostate cancer [13,14]. However, the above-mentioned biomarkers should be examined in cancerous tissues. Moreover, it is difficult to monitor their levels continuously in the process of disease progression. In contrast, the inflammation parameters can be easily assayed in plasma. Therefore, biomarkers should be carefully selected to improve prognostic accuracy. Recently, the Glasgow Prognostic Score has been developed to evaluate the value of an inflammation-based score in patients with metastatic prostate cancer. The Glasgow Prognostic Score, evaluating elevated CRP (>10mg) and hypoalbuminemia (<3.5g), appears to be a useful biomarker in the prognosis of prostate cancer [15]. The possible mechanism by which CRP is associated with the worse outcome in prostate cancer.
• Tumor growth itself can cause inflammation of surrounding tissue and increase CRP [16].
• Tumor cells produce various cytokines and chemokines that attract leukocytes. Some cancer cells express CRP and secrete interleukin-6 and interleukin-8, which stimulate liver CRP production [17]. IL-6 blocks p-53 induced apoptosis. CRP positivity develops a favorable microenvironment for the tumor cells through acute inflammatory cytokine network system maintenance [18].
An elevated CRP identifies those patients with an impaired T-lymphocytic response, since poor infiltration of tumor appears to be associated with poor outcome [19,20]. Liu [21] reported a total of nine studies (n=1497) were evaluated in meta-analysis (five for overall survival (OS), four for CSS (cancer-specific survival) and two for PFS (progression-free survival). They reported that an elevated CRP level could predict poor survival in patients with PCa and associated with OS, CSS and PFS.
In Aldemir's study [22], CRP is significantly higher in the PCa patients with PSA>20ng/ml, compared to the subjects with PSA<20,and is significantly higher in patients with Gleason score>6,comparted to the patients with Gleason score <6. Therefore, they also concluded that elevated CRP level demonstrate their diagnostic value in advanced stage prostate cancer. Thumer [23] evaluated 261 prostate cancer patients treated with 3D-conformal radiotheraphy. They concluded an elevated plasma CRP (>8.6mg) has been identified as a prognostic factor for poor CSS, OS and DFS in prostate cancer patients undergoing radiotherapy. The association between elevated CRP levels and poor prognosis was independent of other measures of prognosis such as tumor stage, Gleason grading and PSA level at diagnosis.
Targeting IL-6, Siltuximab (CNTO328)
If CRP had a specific role in prostate cancer progression and or resistance, direct inhibitors of CRP might make for attractive therapeutic agents. A chimerised monoclonal antibody targeting IL-6, named CNTO328, was developed in recent years. It contains the constant region of a human IgG1 κ immnunoglobulin and the antigen-binding variable region of the murine anti-IL-6 antibody. This feature enables it to inhibit the binding of IL-6 to the IL-6 receptor. This area still holds promise for inhibitors of IL-6 signalling pathways to be anti-metastatic agents, most probably combined with other agents.
Siltuximab (CNTO328), a monoclonal antibody against IL-6, has been studied in combination with chemotherapy [24] and as a single agent [25]. Although these phase 2 studies were not designed to yield definitive results, neither use in combination with mitoxantrone nor single-agent treatment with CNTO 328 appeared to improve clinically important end points, despite the fact that CNTO328 led to expected decrease in IL-6 and CRP.

Conclusion

CRP had a specific role in prostate cancer progression and or resistance. Therefore,inhibitors of CRP (Siltuximab) might make for attractive therapeutic agents. To date, no such agents have been developed. Recently, clinical trial have focused on targeting inflammation. Siltuximab (CNTO328), a monoclonal antibody against IL-6, has been studied in combination with chemotherapy and as a single agent.

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011; 61: 69-90.
  2. Roxburgh CS, McMillan DC. Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Future Oncol. 2010; 6: 149-163.
  3. Mcshane LM, Altman DG, Sauerbrel W. Identification of clinically useful cancer prognostic factors: what are we missing? J Natl Cancer Inst. 2005; 97: 1023-1025.
  4. Morley JJ, Kushner I. Serum C-reactive protein levels in disease. Ann NY Acad Sci. 1982; 389: 406-418.
  5. Bataille R, Klein B. C-reactive protein levels as a direct indicator of interleukin-6 levels in humans in vivo. Arthritis Rheum. 1992; 35: 982-984.
  6. Black S, Kushner I, Samols D. C-reactive protein J Biol Chem. 2004; 279: 48487-48490.
  7. Barber MD FK, Poss JA. Relationship of serum levels of interleukin-6, soluble interleukin-8 receptor and tumor necrosis factor receptors to the acute-phase protein response in advanced pancreatoic cancer. Cli Sci (Lond). 1999; 96: 83-87
  8. Mahmound FA, Rivera NI. The role of c-reactive protein as a prognostic indicator in advanced cancer. Curr Oncol Rep. 2002; 4: 250-255.
  9. Beer TM, Lalani AS, Lee S, Mori M, Eilers KM, Curd JG, et al. C-reactive protein as a prognostic marker for men with androgen-independent prostate cancer: results from the ASCENT trial. Cancer. 2008; 112: 2377- 2383.
  10. Elsberger B, Lankston L, Mcmillen DC, Underwood MA, Edwards J. Presence of tumoural C-reactive protein correlates with progressive prostate cancer. Prostate Cancer Dis. 2011; 14: 122-128.
  11. Glenski WJ, Malek RS, Myrtie JF, Oesterling JE. Sustained, substantially increased concentration of prostate-specific antigen in the absence of prostatic malignant disease:an unusual scenario. Mayo Clin Proc. 1992; 67: 249-252.
  12. Oesterling JE. Prostate-specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. J Urol. 1991; 145: 907-923.
  13. Hayes DF, Isaacs C, Stearms V. Prognostic factors in breast cancer: current and new predictors of metastasis. J Mammary Gland Biol Neoplasia. 2001; 6: 375-392.
  14. Mimeault M, Johansson SL, Batra SK. Pathological implications of the expression of EGFR, pAkt ,NF-κB and MIC-1 in prostate cancer stem cells and their progenies. PLos ONE. 2012; 7: e31919.
  15. Shafique K, Proctor MJ, McMillan DC, Qureshi K, Leung H, Morrison DS. Systemic inflammation and survival of patients with prostate cancer: evidence from the Glasgow Inflammation Outcome Study. Prostate Cancer Prostatic Dis. 2012; 15: 195-201.
  16. Backwill F, Mantovani A. Inflammation and cancer back to Virchow? Lancet. 2001; 17: 539-545.
  17. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002; 420: 860- 867.
  18. Hara M, Yonei A, Ayabe T, Tomita M, Nakamura K, Onitsuka T. Postoperative serum C-reactive protein levels in non-small cell lung cancer patients. Ann Thorac Cardiovas Surg. 2010; 16: 85-90.
  19. Jass JR, Love SB, Northover JM. A new prognostic classification of rectal cancer. Lancet. 1987; 1: 1303-1306.
  20. Nielsen HJ, Hansen U, Christensen IJ, Reimert CM, Brünner N, Moesgaard F. Independent prognostic value of eosinophil and mast cell infiltration in colorectal cancer tissue. J Pathol. 1999; 189: 487-495.
  21. Liu ZQ, Chu L, Fang JM, Zhang Xi, Zhao HX, XU Q. Prognostic role of C-reactive protein in prostate cancer: a systemic review and meta-analysis Asian J Androl. 2014; 16: 467-471.
  22. Aldemir M, Ener K, Dehni D, Ağras K, Kayıgil O. Evaluation of the relationship between prostate cancer and serum inflammation markers. Int J Nephrol Urol. 2010; 2: 244-250.
  23. Thurner EM, Krenn-Pilko S, Langsenlehner U, Stojakovic T, Pichler M, Gerger A, et al. The elevated C-reactive protein level is associated with poor prognosis in prostate cancer patients treated with radiotherapy. Eur J Cancer. 2015; 51: 610-619.
  24. . Fizazi K, De Bono JS, Flechon A, Heidenreich A, Voog E, Davis NB, et al. Randomised phase study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitroxantrone/prednisone verus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. Eur J Cancer. 2012; 48: 85-93.
  25. Dorff TB, Goldman B, Pinski JK, Mack PC, Lara PN Jr, Van Veldhuizen PJ Jr, et al. Clinical and correlative results of SWOG S0354: a phase trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotheraphy pretreated patients with castration-resistant prostate cancer. Clin Cancer Res. 2010; 16: 3028-3034.