Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

C-Reactive Protein Signaling Pathways in Tumor Progression

  • Eun-Sook Kim (Duksung Innovative Drug Center, College of Pharmacy, Duksung Women's University) ;
  • Sun Young Kim (Department of Chemistry, College of Science and Technology, Duksung Women's University) ;
  • Aree Moon (Duksung Innovative Drug Center, College of Pharmacy, Duksung Women's University)
  • Received : 2023.07.19
  • Accepted : 2023.07.27
  • Published : 2023.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Many cancers arise from sites of chronic inflammation, which creates an inflammatory microenvironment surrounding the tumor. Inflammatory substances secreted by cells in the inflammatory environment can induce the proliferation and survival of cancer cells, thereby promoting cancer metastasis and angiogenesis. Therefore, it is important to identify the role of inflammatory factors in cancer progression. This review summarizes the signaling pathways and roles of C-reactive protein (CRP) in various cancer types, including breast, liver, renal, and pancreatic cancer, and the tumor microenvironment. Mounting evidence suggests the role of CRP in breast cancer, particularly in triple-negative breast cancer (TNBC), which is typically associated with a worse prognosis. Increased CRP in the inflammatory environment contributes to enhanced invasiveness and tumor formation in TNBC cells. CRP promotes endothelial cell formation and angiogenesis and contributes to the initiation and progression of atherosclerosis. In pancreatic and kidney cancers, CRP contributes to tumor progression. In liver cancer, CRP regulates inflammatory responses and lipid metabolism. CRP modulates the activity of various signaling molecules in macrophages and monocytes present in the tumor microenvironment, contributing to tumor development, the immune response, and inflammation. In the present review, we overviewed the role of CRP signaling pathways and the association between inflammation and cancer in various types of cancer. Identifying the interactions between CRP signaling pathways and other inflammatory mediators in cancer progression is crucial for understanding the complex relationship between inflammation and cancer.

Keywords

Acknowledgement

The present study was supported by the National Research Foundation of Korea (no. 2016R1A6A1A03007648, no. 2022R1A2C1093335, and no. 2022R1F1A1076029).

References

  1. Abifadel, M., Varret, M., Rabes, J. P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derre, A., Villeger, L., Farnier, M., Beucler, I., Bruckert, E., Chambaz, J., Chanu, B., Lecerf, J., Luc, G., Moulin, P., Weissenbach, J., Prat, A., Krempf, M., Junien, C., Seidah, N. G. and Boileau, C. (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154-156. https://doi.org/10.1038/ng1161
  2. Agresti, R., Meneghini, E., Baili, P., Minicozzi, P., Turco, A., Cavallo, I., Funaro, F., Amash, H., Berrino, F., Tagliabue, E. and Sant, M. (2016) Association of adiposity, dysmetabolisms, and inflammation with aggressive breast cancer subtypes: a cross-sectional study. Breast Cancer Res. Treat. 157, 179-189. https://doi.org/10.1007/s10549-016-3802-3
  3. Akiyama, Y., Griffith, R., Miller, P., Stevenson, G. W., Lund, S., Kanapa, D. J. and Stevenson, H. C. (1988) Effects of adherence, activation and distinct serum proteins on the in vitro human monocyte maturation process. J. Leukoc. Biol. 43, 224-231. https://doi.org/10.1002/jlb.43.3.224
  4. Ames, B. N., Gold, L. S. and Willett, W. C. (1995) The causes and prevention of cancer. Proc. Natl. Acad. Sci. U. S. A. 92, 5258-5265. https://doi.org/10.1073/pnas.92.12.5258
  5. Annex, B. H., Denning, S. M., Channon, K. M., Sketch, M. H., Jr., Stack, R. S., Morrissey, J. H. and Peters, K. G. (1995) Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes. Circulation 91, 619-622. https://doi.org/10.1161/01.CIR.91.3.619
  6. Argiles, J. M., Lopez-Soriano, F. J., Toledo, M., Betancourt, A., Serpe, R. and Busquets, S. (2011) The cachexia score (CASCO): a new tool for staging cachectic cancer patients. J. Cachexia Sarcopenia Muscle 2, 87-93. https://doi.org/10.1007/s13539-011-0027-5
  7. Asegaonkar, S. B., Asegaonkar, B. N., Takalkar, U. V., Advani, S. and Thorat, A. P. (2015) C-reactive protein and breast cancer: new insights from old molecule. Int. J. Breast Cancer 2015, 145647.
  8. Baer, P. C., Gauer, S., Wegner, B., Schubert, R. and Geiger, H. (2006) C-reactive protein induced activation of MAP-K and RANTES in human renal distal tubular epithelial cells in vitro. Clin. Nephrol. 66, 177-183. https://doi.org/10.5414/CNP66177
  9. Balkwill, F. and Mantovani, A. (2001) Inflammation and cancer: back to Virchow? Lancet 357, 539-545. https://doi.org/10.1016/S0140-6736(00)04046-0
  10. Bello, G., Cailotto, F., Hanriot, D., Kolopp-Sarda, M. N., Latger-Cannard, V., Hess, K., Zannad, F., Longrois, D. and Ropars, A. (2008) C-reactive protein (CRP) increases VEGF-A expression in monocytic cells via a PI3-kinase and ERK1/2 signaling dependent pathway. Atherosclerosis 200, 286-293. https://doi.org/10.1016/j.atherosclerosis.2007.12.046
  11. Bian, F., Yang, X. Y., Xu, G., Zheng, T. and Jin, S. (2019) CRP-induced NLRP3 inflammasome activation increases LDL transcytosis across endothelial cells. Front. Pharmacol. 10, 40.
  12. Bisoendial, R. J., Boekholdt, S. M., Vergeer, M., Stroes, E. S. and Kastelein, J. J. (2010) C-reactive protein is a mediator of cardiovascular disease. Eur. Heart J. 31, 2087-2091. https://doi.org/10.1093/eurheartj/ehq238
  13. Blot, W. J., Li, J. Y., Taylor, P. R., Guo, W., Dawsey, S., Wang, G. Q., Yang, C. S., Zheng, S., Gail, M., Li, G., Yu, Y., Liu, B., Tangrea, J., Sun, Y., Liu, F., Fraumeni, J. F., Zhang, Y., Jr. and Li, B. (1993) Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J. Natl. Cancer Inst. 85, 1483-1492. https://doi.org/10.1093/jnci/85.18.1483
  14. Bogaty, P., Brophy, J. M., Noel, M., Boyer, L., Simard, S., Bertrand, F. and Dagenais, G. R. (2004) Impact of prolonged cyclooxygenase-2 inhibition on inflammatory markers and endothelial function in patients with ischemic heart disease and raised C-reactive protein: a randomized placebo-controlled study. Circulation 110, 934-939. https://doi.org/10.1161/01.CIR.0000139338.12464.5F
  15. Bokhari, A. and Tiscornia-Wasserman, P. G. (2017) Cytology diagnosis of metastatic clear cell renal cell carcinoma, synchronous to pancreas, and metachronous to thyroid and contralateral adrenal: report of a case and literature review. Diagn. Cytopathol. 45, 161-167. https://doi.org/10.1002/dc.23619
  16. Boras, E., Slevin, M., Alexander, M. Y., Aljohi, A., Gilmore, W., Ashworth, J., Krupinski, J., Potempa, L. A., Abdulkareem I. A., Elobeid, A. and Matou-Nasri, S. (2014) Monomeric C-reactive protein and Notch-3 co-operatively increase angiogenesis through PI3K signalling pathway. Cytokine 69, 165-179. https://doi.org/10.1016/j.cyto.2014.05.027
  17. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A. and Jemal, A. (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394-424. https://doi.org/10.3322/caac.21492
  18. Calle, E. E. and Kaaks, R. (2004) Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat. Rev. Cancer 4, 579-591. https://doi.org/10.1038/nrc1408
  19. Cervello, M. and Montalto, G. (2006) Cyclooxygenases in hepatocellular carcinoma. World J. Gastroenterol. 12, 5113-5121. https://doi.org/10.3748/wjg.v12.i32.5113
  20. Chambers, A. F., Groom, A. C. and MacDonald, I. C. (2002) Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2, 563-572. https://doi.org/10.1038/nrc865
  21. Chang, M. K., Hartvigsen, K., Ryu, J., Kim, Y. and Han, K. H. (2012) The pro-atherogenic effects of macrophages are reduced upon formation of a complex between C-reactive protein and lysophosphatidylcholine. J. Inflamm. (Lond.) 9, 42.
  22. Chen, J., Gu, Z. and Wu, M. (2016) C-reactive protein can upregulate VEGF expression to promote ADSC-induced angiogenesis by activating HIF-1α via CD64/PI3k/Akt and MAPK/ERK signaling pathways. Stem Cell Res. Ther. 7, 114.
  23. Chen, Y., Wang, J., Yao, Y., Yuan, W., Kong, M., Lin, Y., Geng, D. and Nie, R. U. (2009) Crp regulates the expression and activity of tissue factor as well as tissue factor pathway inhibitor via NF-kappaB and ERK 1/2 MAPK pathway. FEBS Lett. 583, 2811-2818. https://doi.org/10.1016/j.febslet.2009.07.037
  24. Cirillo, P., Golino, P., Calabro, P., Cali, G., Ragni, M., De Rosa, S., Cimmino, G., Pacileo, M., De Palma, R., Forte, L., Gargiulo, A., Corigliano, F. G., Angri, V., Spagnuolo, R., Nitsch, L. and Chiariello, M. (2005) C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation. Cardiovasc. Res. 68, 47-55. https://doi.org/10.1016/j.cardiores.2005.05.010
  25. Coussens, L. M. and Werb, Z. (2002) Inflammation and cancer. Nature 420, 860-867. https://doi.org/10.1038/nature01322
  26. Cui, C. J., Li, S., Zhu, C. G., Sun, J., Du, Y., Zhang, Y., Wu, N., Guo, Y., Xu, R., Gao, Y. and Li, J. (2016) Enhanced pro-protein convertase subtilisin/kexin type 9 expression by C-reactive protein through p38MAPK-HNF1α pathway in HepG2 cells. J. Cell. Mol. Med. 20, 2374-2383. https://doi.org/10.1111/jcmm.12931
  27. Dalpiaz, O., Luef, T., Seles, M., Stotz, M., Stojakovic, T., Pummer, K., Zigeuner, R., Hutterer, G. C. and Pichler, M. (2017) Critical evaluation of the potential prognostic value of the pretreatment-derived neutrophil-lymphocyte ratio under consideration of C-reactive protein levels in clear cell renal cell carcinoma. Br. J. Cancer 116, 85-90. https://doi.org/10.1038/bjc.2016.393
  28. Dasari, A., Shen, C., Halperin, D., Zhao, B., Zhou, S., Xu, Y., Shih, T. and Yao, J. C. (2017) Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 3, 1335-1342. https://doi.org/10.1001/jamaoncol.2017.0589
  29. Daskalakis, K. (2021) Functioning and nonfunctioning pNENs. Curr. Opin. Endocr. Metab. Res. 18, 284-290. https://doi.org/10.1016/j.coemr.2021.04.007
  30. Dehghan, A., Dupuis, J., Barbalic, M., Bis, J. C., Eiriksdottir, G., Lu, C., Pellikka, N., Wallaschofski, H., Kettunen, J., Henneman, P., Baumert, J., Strachan, D. P., Fuchsberger, C., Vitart, V., Wilson, J. F., Pare, G., Naitza, S., Rudock, M. E., Surakka, I., de Geus, E. J., Alizadeh, B. Z., Guralnik, J., Shuldiner, A., Tanaka, T., Zee, R. Y., Schnabel, R. B., Nambi, V., Kavousi, M., Ripatti, S., Nauck, M., Smith, N. L., Smith, A. V., Sundvall, J., Scheet, P., Liu, Y., Ruokonen, A., Rose, L. M., Larson, M. G., Hoogeveen, R. C., Freimer, N. B., Teumer, A., Tracy, R. P., Launer, L. J., Buring, J. E., Yamamoto, J. F., Folsom, A. R., Sijbrands, E. J., Pankow, J., Elliott, P., Keaney, J. F., Sun, W., Sarin, A. P., Fontes, J. D., Badola, S., Astor, B. C., Hofman, A., Pouta, A., Werdan, K., Greiser, K. H., Kuss, O., Meyer zu Schwabedissen, H. E., Thiery, J., Jamshidi, Y., Nolte, I. M., Soranzo, N., Spector, T. D., Volzke, H., Parker, A. N., Aspelund, T., Bates, D., Young, L., Tsui, K., Siscovick, D. S., Guo, X., Rotter, J. I., Uda, M,, Schlessinger, D., Rudan, I., Hicks, A. A., Penninx, B. W., Thorand, B., Gieger, C., Coresh, J., Willemsen, G., Harris, T. B., Uitterlinden, A. G., Jarvelin, M. R., Rice, K., Radke, D., Salomaa, V., Willems van Dijk, K., Boerwinkle, E., Vasan, R. S., Ferrucci, L., Gibson, Q. D., Bandinelli, S., Snieder, H., Boomsma, D. I., Xiao, X., Campbell, H., Hayward, C., Pramstaller, P. P., van Duijn, C. M., Peltonen, L., Psaty, B. M., Gudnason, V., Ridker, P. M., Homuth, G., Koenig, W., Ballantyne, C. M., Witteman, J. C. M., Benjamin, E. J., Perola, M. and Chasman, D. I. (2011) Meta-analysis of genome-wide association studies in > 80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation 123, 731-738. https://doi.org/10.1161/CIRCULATIONAHA.110.948570
  31. Devaraj, S., Du Clos, T. W. and Jialal, I. (2005) Binding and internalization of C-reactive protein by Fcgamma receptors on human aortic endothelial cells mediates biological effects. Arterioscler. Thromb. Vasc. Biol. 25, 1359-1363. https://doi.org/10.1161/01.ATV.0000168573.10844.ae
  32. Dolan, R. D., Lim, J., McSorley, S. T., Horgan, P. G. and McMillan, D. C. (2017) The role of the systemic inflammatory response in predicting outcomes in patients with operable cancer: systematic review and meta-analysis. Sci. Rep. 7, 16717.
  33. Dong, Q. and Wright, J. R. (1996) Expression of C-reactive protein by alveolar macrophages. J. Immunol. 156, 4815-4820. https://doi.org/10.4049/jimmunol.156.12.4815
  34. Dossus, L., Jimenez-Corona, A., Romieu, I., Boutron-Ruault, M. C., Boutten, A., Dupre, T., Fagherazzi, G., Clavel-Chapelon, F. and Mesrine, S. (2014) C-reactive protein and postmenopausal breast cancer risk: results from the E3N cohort study. Cancer Causes Control 25, 533-539. https://doi.org/10.1007/s10552-014-0355-9
  35. Dranoff, G. (2004) Cytokines in cancer pathogenesis and cancer therapy. Nat. Rev. Cancer 4, 11-22. https://doi.org/10.1038/nrc1252
  36. Elston, C. W. and Ellis, I. O. (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19, 403-410. https://doi.org/10.1111/j.1365-2559.1991.tb00229.x
  37. Engelman, J. A., Luo, J. and Cantley, L. C. (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7, 606-619. https://doi.org/10.1038/nrg1879
  38. Falconer, J. S., Fearon, K. C., Ross, J. A., Elton, R., Wigmore, S. J., Garden, O. J. and Carter, D. C. (1995) Acute-phase protein response and survival duration of patients with pancreatic cancer. Cancer 75, 2077-2082. https://doi.org/10.1002/1097-0142(19950415)75:8<2077::AID-CNCR2820750808>3.0.CO;2-9
  39. Febvre-James, M., Lecureur, V. and Fardel, O. (2020) Potent repression of C-reactive protein (CRP) expression by the JAK1/2 inhibitor ruxolitinib in inflammatory human hepatocytes. Inflamm. Res. 69, 51-62. https://doi.org/10.1007/s00011-019-01293-1
  40. Feng, C., Xiong, Z., Jiang, H., Ding, Q., Fang, Z. and Hui, W. (2016) Genetic alteration in notch pathway is associated with better prognosis in renal cell carcinoma. Biofactors 42, 41-48. https://doi.org/10.1002/biof.1250
  41. Flum, A. S., Hamoui, N., Said, M. A., Yang, X. J., Casalino, D. D., McGuire, B. B., Perry, K. T. and Nadler, R. B. (2016) Update on the diagnosis and management of renal angiomyolipoma. J. Urol. 195, 834-846. https://doi.org/10.1016/j.juro.2015.07.126
  42. Folkman, J. (1971) Tumor angiogenesis theraperutic implications. N. Engl. J. Med. 285, 1182-1186. https://doi.org/10.1056/NEJM197108122850711
  43. Frydenberg, H., Thune, I., Lofterod, T., Mortensen, E. S., Eggen, A. E., Risberg, T., Wist, E. A., Flote, V. G., Furberg, A., Wilsgaard, T., Akslen, L. A. and McTiernan, A. (2016) Pre-diagnostic high-sensitive C-reactive protein and breast cancer risk, recurrence, and survival. Breast Cancer Res. Treat. 155, 345-354. https://doi.org/10.1007/s10549-015-3671-1
  44. Fujita, T., Nishi, M., Tabata, K., Matsumoto, K., Yoshida, K. and Iwamura, M. (2016) Overall prognostic impact of C-reactive protein level in patients with metastatic renal cell carcinoma treated with sorafenib. Anticancer Drugs 27, 1028-1032. https://doi.org/10.1097/CAD.0000000000000417
  45. Ghosh, S. and Karin, M. (2002) Missing pieces in the NF-κB puzzle. Cell. 109, 81-96. https://doi.org/10.1016/S0092-8674(02)00703-1
  46. Gomez-Valenzuela, F., Escobar, E., Perez-Tomas, R. and Montecinos, V. P. (2021) The inflammatory profile of the tumor microenvironment, orchestrated by cyclooxygenase-2, promotes epithelial-mesenchymal transition. Front. Oncol. 11, 686792.
  47. Gong, T., Liu, L., Jiang, W. and Zhou, R. (2020) DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95-112. https://doi.org/10.1038/s41577-019-0215-7
  48. Grad, E. and Danenberg, H. D. (2013) C-reactive protein and atherothrombosis: cause or effect? Blood Rev. 27, 23-29. https://doi.org/10.1016/j.blre.2012.12.001
  49. Grivennikov, S. I., Greten, F. R. and Karin, M. (2010) Immunity, inflammation, and cancer. Cell 140, 883-899. https://doi.org/10.1016/j.cell.2010.01.025
  50. Greten, F. and Grivennikov, S. I. (2019) Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51, 27-41. https://doi.org/10.1016/j.immuni.2019.06.025
  51. Guo, S., He, X., Chen, Q., Yang, G., Yao, K., Dong, P., Ye, Y., Chen, D., Zhang, Z., Qin, Z., Liu, Z., Xue, Y., Zhang, M., Liu, R., Zhou, F. and Han, H. (2017) The C-reactive protein/albumin ratio, a validated prognostic score, predicts outcome of surgical renal cell carcinoma patients. BMC Cancer 17, 171.
  52. Hanahan, D. and Weinberg, R. A. (2011) Hallmarks of cancer: the next generation. Cell 144, 646-674. https://doi.org/10.1016/j.cell.2011.02.013
  53. Hansen, I. S., Krabbendam, L., Bernink, J. H., Loayza-Puch, F., Hoepel, W., van Burgsteden, J. A., Kuijper, E. C., Buskens, C. J., Bemelman, W. A., Zaat, S. A. J., Agami, R., Vidarsson, G., van den Brink, G. R., de Jong, E. C., Wildenberg, M. E., Baeten, D., Everts, B. and den Dunnen, J. (2018) FcαRI co-stimulation converts human intestinal CD103+ dendritic cells into pro-inflammatory cells through glycolytic reprogramming. Nat. Commun. 9, 863.
  54. Hashimoto, K., Ikeda, Y., Korenaga, D., Tanoue, K., Hamatake, M., Kawasaki, K., Yamaoka, T., Iwatani, Y., Akazawa, K. and Takenaka, K. (2005) The impact of preoperative serum C-reactive protein on the prognosis of patients with hepatocellular carcinoma. Cancer 103, 1856-1864. https://doi.org/10.1002/cncr.20976
  55. Hansson, G. K. (2005) Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352, 1685-1695. https://doi.org/10.1056/NEJMra043430
  56. Hattori, Y., Matsumura, M. and Kasai, K. (2003) Vascular smooth muscle cell activation by C-reactive protein. Cardiovasc. Res. 58, 186-195. https://doi.org/10.1016/S0008-6363(02)00855-6
  57. He, Y., Sun, M. M., Zhang, G. G., Yang, J., Chen, K. S., Xu, W. W. and Li, B. (2021) Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct. Target. Ther. 6, 425.
  58. Hojilla, C. V., Wood, G. A. and Khokha, R. (2008) Inflammation and breast cancer: metalloproteinases as common effectors of inflammation and extracellular matrix breakdown in breast cancer. Breast Cancer Res. 10, 205.
  59. Hong, T., Liu, A., Cai, D., Zhang, Y., Hua, D., Hang, X. and Wu, X. (2013) Preoperative serum C-reactive protein levels and early breast cancer by BMI and menopausal status. Cancer Invest. 31, 279-285. https://doi.org/10.3109/07357907.2013.789898
  60. Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J. and Thun, M. J. (2007) Cancer statistics. CA Cancer J. Clin. 57, 43-66. https://doi.org/10.3322/canjclin.57.1.43
  61. Kim, E. S., Cha, Y., Ham, M., Jung, J., Kim, S. G., Hwang, S., Kleemann, R. and Moon, A. (2014) Inflammatory lipid sphingosine1-phosphate upregulates C-reactive protein via C/EBPβ and potentiates breast cancer progression. Oncogene 33, 3583-3593. https://doi.org/10.1038/onc.2013.319
  62. Kim, E. S., Kim, S. Y., Koh, M., Lee, H. M., Kim, K., Jung, J., Kim, H. S., Moon, W. K., Hwang, S. and Moon, A. (2018) C-reactive protein binds to integrin α2 and Fcγ receptor I, leading to breast cell adhesion and breast cancer progression. Oncogene 4, 28-38. https://doi.org/10.1038/onc.2017.298
  63. Kishi, T., Nakamura, A., Itasaka, S., Shibuya, K., Matsumoto, S., Kanai, M., Kodama, Y., Takaori, K., Mizowaki, T. and Hiraoka, M. (2015) Pretreatment C-reactive protein level predicts outcome and patterns of failure after chemoradiotherapy for locally advanced pancreatic cancer. Pancreatology 15, 694-700. https://doi.org/10.1016/j.pan.2015.09.016
  64. Kleemann, R., Gervois, P. P., Verschuren, L., Staels, B., Princen, H. M. and Kooistra, T. (2003) Fibrates downregulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFκB-C/EBP-β complex formation. Blood 101, 545-551. https://doi.org/10.1182/blood-2002-06-1762
  65. Krupinski, J., Turu, M. M., Martinez-Gonzalez, J., Carvajal, A., Juan-Babot, J. O., Iborra, E., Slevin, M., Rubio, F. and Badimon, L. (2006) Endogenous expression of C-reactive protein is increased in active (ulcerated oncomplicated) human carotid artery plaques. Stroke 37, 1200-1204. https://doi.org/10.1161/01.STR.0000217386.37107.be
  66. Kumar, H., Kawai, T. and Akira, S. (2009) Toll-like receptors and innate immunity. Biochem. Biophys. Res. Commun. 388, 621-625. https://doi.org/10.1016/j.bbrc.2009.08.062
  67. Lee, J. G., Cho, B. C., Bae, M. K., Lee, C. Y., Park, I. K., Kim, D. J., Ahn, S. V. and Chung, K. Y. (2009) Preoperative C-reactive protein levels are associated with tumor size and lymphovascular invasion in resected non-small cell lung cancer. Lung Cancer 63, 106-110. https://doi.org/10.1016/j.lungcan.2008.04.011
  68. Levy, D. E. and Darnell, J. E., Jr. (2002) Stats: transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol. 3, 651-662. https://doi.org/10.1038/nrm909
  69. Li, J., Luo, S. H., Tang, Y. and Li, J. J. (2014) C-reactive protein induces pulmonary artery smooth cell proliferation via modulation of ERK1/2, Akt and NF-kappaB pathways. Clin. Lab. 60, 1357-1363.
  70. Liang, Y. J., Shyu, K. G., Wang, B. W. and Lai, L. P. (2006) C-reactive protein activates thenuclear factor-kB pathway andinduces vascular cell adhesion molecule-1expression through CD32 inhuman umbilical vein endothelial cells andaortic endothelial cells. J. Mol. Cell. Cardiol. 40, 412-420. https://doi.org/10.1016/j.yjmcc.2005.12.008
  71. Libby, P. (2002) Inflammation in atherosclerosis. Nature 420, 868-874. https://doi.org/10.1038/nature01323
  72. Lithgow, D., Nyamathi, A., Elashoff, D., Martinez-Maza, O. and Covington, C. (2006) C-reactive protein in nipple aspirate fluid. Nurs. Res. 65, 418-425.
  73. Liu, X. Y., Yan, F., Niu, L. L., Chen, Q. N., Zheng, H. R. and Li, J. Y. (2016) Strong correlation between early stage atherosclerosis and electromechanical coupling of aorta. Nanoscale 8, 6975-6980. https://doi.org/10.1039/C5NR07398G
  74. Ma, Z., Qi, Z., Shan, Z., Li, J., Yang, J. and Xu, Z. (2017) The role of CRP and ATG9B expression in clear cell renal cell carcinoma. Biosci. Rep. 37, BSR20171082.
  75. Maekawa, H. and Tollefsen, D. M. (1996) Role of proposed serpin-enzyme complex receptor recognition sites in binding and internalization of thrombin-heparin cofactor II complexes by hepatocytes. J. Biol. Chem. 271, 18604-18609. https://doi.org/10.1074/jbc.271.31.18604
  76. Majello, B., Arcone, R., Toniatti, C. and Ciliberto, G. (1990) Constitutive and IL-6 induced nuclear factors that interact with the human C-reactive protein promoter. EMBO J. 9, 457-465. https://doi.org/10.1002/j.1460-2075.1990.tb08131.x
  77. Mannello, F., Tonti, G. A., Simone, P., Ligi, D. and Medda, V. (2010) Iron-binding proteins and C-reactive protein in nipple aspirate fluids: role of iron-driven inflammation in breast cancer microenvironment? Am. J. Transl. Res. 3, 100-113.
  78. Manning, B. D. and Cantley, L. C. (2007) AKT/PKB signaling: navigating downstream. Cell 129, 1261-1274. https://doi.org/10.1016/j.cell.2007.06.009
  79. Mantovani, A., Allavena, P., Sica, A. and Balkwill, F. (2008) Cancer-related inflammation. Nature 454, 436-444. https://doi.org/10.1038/nature07205
  80. Martin-Timon, I., Sevillano-Collantes, C., Segura-Galindo, A. and Del Canizo-Gomez, F. J. (2014) Type 2 diabetes and cardiovascular disease: Have all risk factors the same strength? World J. Diabetes 5, 444-470. https://doi.org/10.4239/wjd.v5.i4.444
  81. McCarthy, C. G., Goulopoulou, S., Wenceslau, C. F., Spitler, K., Matsumoto, T. and Webb, R. C. (2014) Toll-like receptors and damage-associated molecular patterns: novel links between inflammation and hypertension. Am. J. Physiol. Heart Circ. Physiol. 306, H184-H196. https://doi.org/10.1152/ajpheart.00328.2013
  82. Metzger-Filho, O., Tutt, A., de Azambuja, E., Saini, K. S., Viale, G., Loi, S., Bradbury, I., Bliss, J. M., Azim, H. J., Jr., Ellis, P., Di Leo, A., Baselga, J., Sotiriou, C. and Piccart-Gebhart, M. (2012) Dissecting the heterogeneity of triple-negative breast cancer. J. Clin. Oncol. 30, 1879-1887. https://doi.org/10.1200/JCO.2011.38.2010
  83. Moscat, J., Diaz-Meco, M. T., and Rennert, P. (2003) NFκB activation by protein kinase C isoforms and B-cell function. EMBO Rep. 4, 31-36. https://doi.org/10.1038/sj.embor.embor704
  84. Nakachi, K., Furuse, J., Ishii, H., Suzuki, E. and Yoshino, M. (2007) Prognostic factors in patients with gemcitabine-refractory pancreatic cancer. Jpn. J. Clin. Oncol. 37, 114-120. https://doi.org/10.1093/jjco/hyl144
  85. Newling, M., Sritharan, L., van der Ham, A. J., Hoepel, W., Fiechter, R. H., de Boer, L., Zaat, S. A. J., Bisoendial, R. J., Baeten, D. L. P., Everts, B. and den Dunnen, J. (2019) C-reactive protein promotes inflammation through FcγR-induced glycolytic reprogramming of human macrophages. J. Immunol. 203, 225-235. https://doi.org/10.4049/jimmunol.1900172
  86. Nikolaou, K., Sarris, M. and Talianidis, I. (2013) Molecular pathways: the complex roles of inflammation pathways in the development and treatment of liver cancer. Clin. Cancer Res. 19, 2810-2816. https://doi.org/10.1158/1078-0432.CCR-12-1961
  87. Overall, C. M. and Lopez-Otin, C. (2002) Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat. Rev. Cancer 2, 657-672. https://doi.org/10.1038/nrc884
  88. Ozturk, H. (2015) Bilateral synchronous adrenal metastases of renal cell carcinoma: a case report and review of the literature. Oncol. Lett. 9, 1897-1901. https://doi.org/10.3892/ol.2015.2915
  89. Paffen, E., Vos, H. L. and Bertina, R. M. (2004) C-reactive protein does not directly induce tissue factor in human monocytes. Arterioscler. Thromb. Vasc. Biol. 24, 975-981. https://doi.org/10.1161/01.ATV.0000126681.16619.69
  90. Park, W. B., Lee, K. D., Lee, C. S., Jang, H. C., Kim, H. B., Lee, H. S., Oh, M. and Choe, K. W. (2005) Production of C-reactive protein in Escherichia coli-infected patients with liver dysfunction due to liver cirrhosis. Diagn. Microbiol. Infect. Dis. 51, 227-230. https://doi.org/10.1016/j.diagmicrobio.2004.11.014
  91. Pasceri, V., Willerson, J. T. and Yeh, E. T. (2000) Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 102, 2165-2168. https://doi.org/10.1161/01.CIR.102.18.2165
  92. Pasceri, V., Cheng, J. S., Willerson, J. T. and Yeh, E. T. (2001) Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation 103, 2531-2534. https://doi.org/10.1161/01.CIR.103.21.2531
  93. Pawashe, A. B., Golino, P., Ambrosio, G., Migliaccio, F., Ragni, M., Pascucci, I., Chiariello, M., Bach, R., Garen, A. and Konigsberg, W. K. (1994) A monoclonal antibody against rabbit tissue factor inhibits thrombus formation in stenotic injured rabbit carotid arteries. Circ. Res. 74, 56-63. https://doi.org/10.1161/01.RES.74.1.56
  94. Pena, E., de la Torre, R., Arderiu, G., Slevin, M. and Badimon, L. (2016) mCRP triggers angiogenesis by inducing F3 transcription and TF signalling in microvascular endothelial cells. Thromb. Haemost. 117, 357-370.
  95. Pepys, M. B. and Hirschfield, G. M. (2003) C-reactive protein: a critical update. J. Clin. Invest. 111, 1805-1812. https://doi.org/10.1172/JCI200318921
  96. Pierce, B. L., Ballard-Barbash, R., Bernstein, L., Baumgartner, R. N., Neuhouser, M. L., Wener, M. H., Baumgartner, K. B., Gilliland, F. D., Sorensen, B. E., McTiernan, A. and Ulrich, C. M. (2009) Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J. Clin. Oncol. 27, 3437-3444. https://doi.org/10.1200/JCO.2008.18.9068
  97. Pine, J. K., Fusai, K. G., Young, R., Sharma, D., Davidson, B. R., Menon, K. V. and Rahman, S. H. (2009) Serum C-reactive protein concentration and the prognosis of ductal adenocarcinoma of the head of pancreas. Eur. J. Surg. Oncol. 35, 605-610. https://doi.org/10.1016/j.ejso.2008.12.002
  98. Platz, E. A. and De Marzo, A. M. (2004) Epidemiology of inflammation and prostate cancer. J. Urol. 171, S36-S40. https://doi.org/10.1097/01.ju.0000108131.43160.77
  99. Prakash, A. V., Park, I. H., Park, J. W., Bae, J. P., Lee, G. S. and Kang, T. J. (2023) NLRP3 inflammasome as therapeutic targets in inflammatory diseases. Biomol. Ther. (Seoul) 31, 395-401. https://doi.org/10.4062/biomolther.2023.099
  100. Raaz-Schrauder, D., Ekici, A. B., Klinghammer, L., Stumpf, C., Achenbach, S., Herrmann, M., Reis, A. and Garlichs, C. D. (2014) The proinflammatory effect of c-reactive protein on human endothelial cells depends on the Fcγ IIa genotype. Thromb. Res. 133, 426-432. https://doi.org/10.1016/j.thromres.2013.12.030
  101. Ravishankaran, P. and Karunanithi, R. (2011) Clinical significance of preoperative serum interleukin-6 and C-reactive protein level in breast cancer patients. World J. Surg. Oncol. 9, 18.
  102. Roxburgh, C. S. D. and McMillan, D. C. (2010) Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Future Oncol. 6, 149-163. https://doi.org/10.2217/fon.09.136
  103. Schecter, A. D., Giesen, P. L., Taby, O., Rosenfield, C. L., Rossikhina, M., Fyfe, B. S., Kohtz, D. S., Fallon, J. T., Nemerson, Y. and Taubman, M. B. (1997) Tissue factor expression in human arterial smooth muscle cells. J. Clin. Invest. 100, 2276-2285. https://doi.org/10.1172/JCI119765
  104. Schenten, D. and Medzhitov, R. (2011) The control of adaptive immune responses by the innate immune system. Adv. Immunol. 109, 87-124. https://doi.org/10.1016/B978-0-12-387664-5.00003-0
  105. Schimmack, S., Yang, Y., Felix, K., Herbst, M., Li, Y., Schenk, M., Bergmann, F., Hackert, T., Strobel, O. and Yang, Y. (2019) C-reactive protein (CRP) promotes malignant properties in pancreatic neuroendocrine neoplasms. Endocr. Connect. 8, 1007-1019. https://doi.org/10.1530/EC-19-0132
  106. Serbulea, V., Upchurch, C. M., Ahern, K. W., Bories, G., Voigt, P., DeWeese, D. E., Meher, A. K., Harris, T. E. and Leitinger, N. (2018) Macrophages sensing oxidized DAMPs reprogram their metabolism to support redox homeostasis and inflammation through a TLR2-Syk-ceramide dependent mechanism. Mol. Metab. 7, 23-34. https://doi.org/10.1016/j.molmet.2017.11.002
  107. Shibutani, M., Maeda, K., Nagahara, H., Iseki, Y., Ikeya, T. and Hirakawa, K. (2016) Prognostic significance of the preoperative ratio of C-reactive protein to albumin in patients with colorectal cancer. Anticancer Res. 36, 995-1001.
  108. Shrotriya, S., Walsh, D., Bennani-Baiti, N., Thomas, S. and Lorton, C. (2015) C-reactive protein is an important biomarker for prognosis tumor recurrence and treatment response in adult solid tumors: a systematic review. PLoS One 10, e0143080.
  109. Siegel, R. L., Miller, K. D. and Jemal, A. (2016) Cancer statistics, 2016. CA Cancer J. Clin. 66, 7-30. https://doi.org/10.3322/caac.21332
  110. Siegel, R. L., Miller, K. D. and Jemal, A. (2019) Cancer statistics, 2019. CA Cancer J. Clin. 69, 7-34. https://doi.org/10.3322/caac.21551
  111. Sieghart, W., Pinter, M., Hucke, F., Graziadei, I., Schoniger-Hekele, M., Muller, C., Vogel, W., Trauner, M. and Peck-Radosavljevic, M. (2013) Single determination of C-reactive protein at the time of diagnosis predicts long-term outcome of patients with hepatocellular carcinoma. Hepatology 57, 2224-2234. https://doi.org/10.1002/hep.26057
  112. Singh, U., Devaraj, S. and Jialal, I. (2005) C-reactive protein decreases tissue plasminogen activator activity in human aortic endothelial cells: evidence that c-reactive protein is a procoagulant. Arterioscler. Thromb. Vasc. Biol. 25, 2216-2221. https://doi.org/10.1161/01.ATV.0000183718.62409.ea
  113. Slevin, M., Matou-Nasri, S., Turu, M., Luque, A., Rovira, N. and Badimon, L. (2010) Modified C-reactive protein is expressed by stroke neovessels and is a potent activator of angiogenesis in vitro. Brain Pathol. 20, 151-165. https://doi.org/10.1111/j.1750-3639.2008.00256.x
  114. Slevin, M., Matou, S., Zeinolabediny, Y., Corpas, R., Weston, R., Liu, D., Boras, E., Di Napoli, M., Petcu, E., Sarroca, S., Popa-Wagner, A., Love, S., Font, M. A., Potempa, L. A., Al-Baradie, R., Sanfeliu, C., Revilla, S., Badimon, L. and Krupinski, J. (2015) Monomeric C-reactive protein-a key molecule driving development of Alzheimer's disease associated with brain ischaemia? Sci. Rep. 5, 13281.
  115. Su, T. T., Guo, B., Kawakami, Y., Sommer, K., Chae, K., Humphries, L. A., Kato, R. M., Kang, S., Patrone, L., Wall, R., Teitell, M., Leitges, M., Kawakami, T. and Rawlings, D. J. (2002) PKC-β controls IκB kinase lipid raft recruitment and activation in response to BCR signaling. Nat. Immunol. 3, 780-786. https://doi.org/10.1038/ni823
  116. Subbaramaiah, K., Morris, P. G., Zhou, X. K., Morrow, M., Du, B., Giri, D., Kopelovich, L., Hudis, C. A. and Dannenberg, A. J. (2012) Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women. Cancer Discov. 2, 356-365. https://doi.org/10.1158/2159-8290.CD-11-0241
  117. Sun, J., Russell, C. C., Scarlett, C. J. and McCluskey, A. (2020) Small molecule inhibitors in pancreatic cancer. RSC Med. Chem. 11, 164-183. https://doi.org/10.1039/C9MD00447E
  118. Sundgren, N. C., Zhu, W., Yuhanna, I. S., Chambliss, K. L., Ahmed, M., Tanigaki, K., Umetani, M., Mineo, C. and Shaul, P. W. (2011) Coupling of Fcγ receptor I to Fcγ receptor IIb by src kinase mediates c-reactive protein impairment of endothelial function. Circ. Res. 109, 1132-1140. https://doi.org/10.1161/CIRCRESAHA.111.254573
  119. Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A. and Bray, F. (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209-249 https://doi.org/10.3322/caac.21660
  120. Tabas, I., Garcia-Cardena, G. and Owens, G. K. (2015) Recent insights into the cellular biology of atherosclerosis. J. Cell Biol. 209, 13-22. https://doi.org/10.1083/jcb.201412052
  121. Takeuchi, O. and Akira, S. (2010) Pattern recognition receptors and inflammation. Cell 140, 805-820. https://doi.org/10.1016/j.cell.2010.01.022
  122. Tang, D., Kang, R., Coyne, C. B., Zeh, H. J. and Lotze, M. T. (2012) PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol. Rev. 249, 158-175. https://doi.org/10.1111/j.1600-065X.2012.01146.x
  123. Tang, Z., Sheng, H., Zheng, X., Ying, L., Wu, L., Liu, D. and Liu, G. (2015) Upregulation of circulating cytokeratin 20, urokinase plasminogen activator and C-reactive protein is associated with poor prognosis in gastric cancer. Mol. Clin. Oncol. 3, 1213-1220. https://doi.org/10.3892/mco.2015.624
  124. Terada, K., Hayashi, G. and Hokama, Y. (1990) C-reactive protein and 6-keto prostaglandin F 1-alpha in patients with gynecologic cancer. Gynecol. Oncol. 36, 212-214. https://doi.org/10.1016/0090-8258(90)90175-K
  125. Toi, M., Inada, K., Suzuki, H. and Tominaga, T. (1995) Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res. Treat. 36, 193-204. https://doi.org/10.1007/BF00666040
  126. Toniatti, C., Demartis, A., Monaci, P., Nicosia, A. and Ciliberto, G. (1990) Synergistic transactivation of the human C-reactive protein promoter by transcription factor HNF-1 binding at two distinct sites. EMBO J. 9, 4467-4475. https://doi.org/10.1002/j.1460-2075.1990.tb07897.x
  127. Turu, M. M., Slevin, M., Matou, S., West, D., Rodriguez, C. and Luque, A. (2008) C-reactive protein exerts angiogenic effects on vascular endothelial cells and modulates associated signalling pathways and gene expression. BMC Cell Biol. 9, 47.
  128. van den Eijnden, M. M., Steenhauer, S. I., Reitsma, P. H. and Bertina, R. M. (1997) Tissue factor expression during monocyte-macrophage differentiation. Thromb. Heamost. 77, 1129-1136. https://doi.org/10.1055/s-0038-1656125
  129. Varga, J. and Greten, F. R. (2017) Cell plasticity in epithelial homeostasis and tumorigenesis. Nat. Cell Biol. 19, 1133-1141. https://doi.org/10.1038/ncb3611
  130. Vergadi, E., Ieronymaki, E., Lyroni, K., Vaporidi, K. and Tsatsanis, C. (2017) Akt signaling pathway in macrophage activation and M1/M2 polarization. J. Immunol. 198, 1006-1014. https://doi.org/10.4049/jimmunol.1601515
  131. Verma, A. K., Kumar, S., Kumar, N., Verma, R. K. and Singh, M. (2012) Study of coronary artery atherosclerosis in sudden deaths and its medicolegal relevance. J. Indian Acad. Forensic Med. 34, 132-134.
  132. Volanakis, J. E. (2001) Human C-reactive protein: expression, structure, and function. Mol. Immunol. 38, 189-197. https://doi.org/10.1016/S0161-5890(01)00042-6
  133. Wang, C. S. and Sun, C. F. (2009) C-reactive protein and malignancy: clinico-pathological association and therapeutic implication. Chang Gung Med. J. 32, 471-482.
  134. Wang, H. R., Chen, D. L., Zhao, M., Shu, S. W., Xiong, S. X., Gan, X. D., Chao, S. and Cao, J. (2012) C-reactive protein induces interleukin-6 and thrombospondin-1 protein and mRNA expression through activation of nuclear factor-κB in HK-2 cells. Kidney Blood Press. Res. 35, 211-219.
  135. Weinhold, B. and Ruther, U. (1997) Interleukin-6-dependent and -independent regulation of the human C-reactive protein gene. Biochem. J. 327, 425-429. https://doi.org/10.1042/bj3270425
  136. Wiese, D., Kampe, K., Waldmann, J., Heverhagen, A. E., Bartsch, D. K. and Fendrich, V. (2016) C-reactive protein as a new prognostic factor for survival in patients with pancreatic neuroendocrine neoplasia. J. Clin. Endocrinol. Metab. 101, 937-944. https://doi.org/10.1210/jc.2015-3114
  137. Wigmore, S. J., Fearon, K. C., Maingay, J. P., Lai, P. B. and Ross, J. A. (1997) Interleukin-8 can mediate acute-phase protein production by isolated human hepatocytes. Am. J. Physiol. 273, 720-726.
  138. Wilcox, J. N., Smith, K. M., Schwartz, S. and Gordon, D. (1989) Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc. Natl. Acad. Sci. U. S. A. 86, 2839-2843. https://doi.org/10.1073/pnas.86.8.2839
  139. Wolf, S., Obolonczyk, L., Sworczak, K., Czapiewski, P. and Sledzinski, Z. (2015) Renal cell carcinoma metastases to the pancreas and the thyroid gland 19 years after the primary tumour. Prz. Gastroenterol. 10, 185-189. https://doi.org/10.1007/s11377-015-0988-6
  140. Wu, Y., Fu, X., Zhu, X., He, X., Zou, C., Han, Y., Xu, M., Huang, C., Lu, X. and Zhao, Y. (2011) Prognostic role of systemic inflammatory response in renal cell carcinoma: a systematic review and meta-analysis. J. Cancer Res. Clin. Oncol. 137, 887-896. https://doi.org/10.1007/s00432-010-0951-3
  141. Yasojima, K., Schwab, C., McGeer, E. G. and McGeer, P. L. (2001) Generation of C-reactive protein and complement components in atherosclerotic plaques. Am. J. Pathol. 158, 1039-1051. https://doi.org/10.1016/S0002-9440(10)64051-5
  142. Yu, H., Pardoll, D. and Jove, R. (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 361-367. https://doi.org/10.1038/nrc2628
  143. Zavodszky, E., Vicinanza, M. and Rubinsztein, D. C. (2013) Biology and trafficking of ATG9 and ATG16L1, two proteins that regulate autophagosome formation. FEBS Lett. 587, 1988-1996. https://doi.org/10.1016/j.febslet.2013.04.025
  144. Zhang, Z., Yang, Y., Hill, M. A. and Wu, J. (2012) Does c-reactive protein contribute to atherothrombosis via oxidant-mediated release of pro-thrombotic factors and activation of platelets? Front. Physiol. 3, 433.