Abstract
COX2 and PPARG are differentially expressed in many human tumors and have emerged as potential targets of biomodulatory cancer therapy. Using three tissue microarrays (TMA) we studied the correlation of COX2/PPARG immunoreactivity in a broad spectrum of tumors focussing on the correlation between clinico-pathologic features and outcome of patients with malignant melanoma (MM).
TMA-1 consisted of normal and tumor tissues (n = 3,448) from 47 organs and tissue entities including skin neoplasms (n = 323) of melanocytic (MM, benign nevi) and non-melanocytic origin (squamous cell carcinomas, basal cell carcinomas, Kaposi sarcomas, histiocytomas, capillary hemangiomas, sebaceous adenomas). TMA-2 consisted of 88 MM with follow-up data, 101 MM metastases and 161 benign nevi. TMA-3 (n = 194) consisted of MM metastases from 36 patients with metastatic stage IV melanoma who had participated in a randomized phase II trial using a stroma-directed biomodulatory approach combining COX/PPAR-targeting with metronomic low-dose chemotherapy.
COX2 immunoreactivity significantly increased from benign nevi (51%) to primary MM (86%) and MM metastases (91%; P < 0.001, TMA-2). In case of primary MM, positive COX2 staining was associated with advanced Clark levels (P= 0.004) and shorter recurrence free survival (P= 0.03). Similarly, PPARG immunoreactivity was significantly increasing from benign nevi (0%) to MM (22%) and MM metastases (33%; P< 0.001). However, PPARG expression in primary MM was not associated with any of the clinico-pathologic characteristics or tumor progression and overall survival. On the other hand, patients with PPARG-positive MM metastases who had been treated either with biomodulatory metronomic chemotherapy (trofosfamide) alone or combined with COX2/PPARG-targeting drugs, i.e. rofecoxib and pioglitazone, showed a significant advantage concerning progression-free survival (P= 0.044).
We conclude that the expression of COX2 and PPARG is a frequent finding in the progression of MM. Regarding primary MM, the expression of COX2 indicates an increased risk of tumor recurrence, i.e. melanoma progression. In metastatic MM the expression of PPARG may serve as positive predictive marker of potential responsiveness to biomodulatory stroma-targeted therapy (Meyer S, Vogt T, Landthaler M, et al (2009). Cyclooxygenase 2 (COX2) and Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Are Stage-Dependent Prognostic Markers of Malignant Melanoma. PPAR Res 2009: 848645).
*Both authors contributed equally
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Abbreviations
- MM:
-
Malignant melanoma
- TMA:
-
Tissue microarray
- IHC:
-
Immunohistochemistry
- COX2:
-
Cyclooxygenase 2
- PPARG:
-
Peroxisome proliferator-activated receptor gamma
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Acknowledgements
We thank Frank van Rey, Lydia Kuenzel and Rudolf Jung for excellent technical assistance.
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Meyer, S. et al. (2010). Cyclooxygenase 2 (COX2) and Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Are Stage-Dependent Prognostic Markers of Malignant Melanoma. In: Reichle, A. (eds) From Molecular to Modular Tumor Therapy. The Tumor Microenvironment, vol 3. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9531-2_22
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DOI: https://doi.org/10.1007/978-90-481-9531-2_22
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