Acute Phase Response Induction by Cancer Treatmen with Photodynamic Therapy

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Slide 1 : ACUTE PHASE RESPONSE INDUCTION BY CANCER TREATMENT WITH PHOTODYNAMIC THERAPY Mladen Korbelik, Ivana Cecic, Soroush Merchant and Jinghai Sun British Columbia Cancer Agency Vancouver B.C., Canada Int. J. Cancer, 122: 1411-1417 (2008)
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Slide 3 : Host response associated with tumor PDT
Slide 4 : Acute phase response A dynamic homeostatic process that can be regarded as a stress response at the level of the organism raised with the purpose of creating an overall protective systemic environment required for coping with tissue injury and containing the disrupted homeostasis. Orchestrated by innate immune system; linked with inflammatory response Triggered by cytokines IL6, IL1, TNF? Systemic changes (distant from PDT-treated site: i) the production and release of acute phase rectants (major source hepatocytes) ii) the activation of pituitary/adrenal gland axis iii) increased numbers of peripheral neutrophils First reported from a study of normal mouse peritoneum PDT treatment (Jolles JC, Ott MJ, Straight RC & Lunch DH, Am J Obstet Gynecol 1988; 158:1446-1453)
Slide 5 : Evidence of blood neutrophilia and associated activity of adrenal hormones (two major hallmarks of acute phase response) induced by tumor treatment with PDT:
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Slide 7 : FsaR fibrosarcomas PDT: Photofrin 10 mg/kg; 150 J/cm2 Untreated tumor 24 hours after PDT SAP immunohistochemistry
Slide 8 : FsaR fibrosarcomas PDT: Photofrin 10 mg/kg; 150 J/cm2 Mannose-binding lectin (MBL): another acute phase reactant induced by tumor PDT in mice PDT-treated tumors
Slide 9 : FsaR fibrosarcomas PDT: Photofrin 10 mg/kg; 150 J/cm2 Mifepristone = glucocorticoid receptor antagonist Role of IL6 and glucocorticoids in PDT-induced SAP gene upregulation
Slide 10 : CONCLUSIONS Treatment of tumors by PDT induces a strong acute phase response in the host mice, manifested as the elevated production of acute phase reactants (in the liver and other sites), release of adrenal glucocortidoid hormones, and peripheral blood neutrophilia. The upregulation of genes encoding acute phase reactants SAP and MBL-A in the liver of mice bearing PDT-treated tumors is accompanied with a marked rise in the serum levels of these proteins and their accumulation in the targeted tumors. However, SAP and MBL-A genes were found to be also upregulated in PDT-treated tumors, which suggests that the production of these acute phase reactants at this site may have an important contribution to their local availability. Glucocorticoid hormones and IL6 were identified as major mediators responsible for the liver SAP gene upregulation in mice bearing PDT-treated tumors; moreover, glucocorticoids are unveiled as major inducers of SAP gene upregulation in PDT-treated tumors. This alerts to the possibility that glucocorticoid hormones can have an important impact on the expression of various genes in PDT-treated tumors. The induced acute phase response emerges as an important element of the response of tumors to PDT and possibly other forms of cancer therapy.

 


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