Molecular analysis of xenograft models of human cancer cachexia--possibilities for therapeutic intervention.
Approximately 50% of all cancer patients develop cachexia, a paraneoplastic syndrome that is characterized by wasting of adipose tissue and skeletal muscle mass. Cytokines, including TNF-alpha, interleukins-1, -6, and interferon-A are known mediators of the cachectic process. The latter however represent only one of many imbalanced systems in cancer cachexia. The aim of this study was to further delineate the pathogenesis of cachexia by molecular profiling. Human renal cancer xenografts that do and do not induce cachexia in mice were used as disease models. Cachexia-associated gene expression was studied on Human Genome U95 Affymetrix arrays and revealed several new genes such as TNF-alpha ligand superfamily protein, interferon-A treatment inducible protein, and DKFZ5641I1922. The expression of the IL-8 gene was also elevated in cachexia inducing xenografts (CIX). At the protein level, TNF-alpha was found expressed only in CIX, whereas IL-1 and IL-6 were not cachexia specific. Levels of parathyroid hormone-related protein were elevated in CIX and accompanied by hypercalcemia. COX-2 and prostaglandin E2 were also found to be over expressed. By using the COX-2 inhibitors rofecoxib and nimesulide, we were able to delay tumor-mediated wasting in vivo. Overall, our results suggest that cachexia is a multigenetic disease that will require complex combinations of drugs for an effective therapeutic intervention.
Baumgarten
Axel J
AJ
Institute for Experimental Oncology, Oncotest GmbH, Am Flughafen 12-14, D-79108 Freiburg, Germany.
Fiebig
Heinz-Herbert
HH
Burger
Angelika M
AM
D000818:Animals; D002100:Cachexia / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006934:Hypercalcemia / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010257:Paraneoplastic Syndromes / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000096:biosynthesis / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use; D014183:Transplantation, Heterologous
D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D007783:Lactones; D044162:Parathyroid Hormone-Related Protein; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone; C012655:nimesulide