Caffeine suppresses metastasis in a transgenic mouse model: a prototype molecule for prophylaxis of metastasis.
A significant fraction of cancer patients have occult disseminated tumors at the time of primary diagnosis, which usually progress to become clinically relevant lesions. Since the majority of cancer mortality is associated with metastatic disease, the ability to inhibit the growth of the secondary tumors would significantly reduce cancer-related morbidity and mortality. We have investigated whether caffeine, which has been shown to suppress tumor cell invasiveness and experimental metastasis, can suppress metastasis in a spontaneous transgene-induced mammary tumor model. Chronic exposure to caffeine prior to the appearance of palpable mammary tumors significantly reduced both tumor burden and metastatic colonization. However, when caffeine exposure began after the appearance of frank tumors, caffeine suppressed metastasis without changing primary tumor burden. The means by which caffeine suppressed metastatic activity may be associated with inhibition of malignant transformation of mammary epithelial cells, inhibition of conversion of dormant tumor cells to micrometastases, micrometastases to macrometastases, or inhibition of tumor cell adhesion and motility. Gene and protein expression patterns resulting from caffeine treatment showed that metastasis suppression may be associated with up-regulation the mRNA expression of multiple extracellular matrix genes, including Fbln1, Bgn, Sparc, Fbn1, Loxl1, Colla1, Col3a1, Col5a1, ColS5a2, ColSa3, Col6a1, Col6a2, and Col6a3. These data suggested that caffeine or other methyl xanthine derivatives may improve the clinical outcome in patients prior to and following the diagnosis of metastatic disease, and could potentially reduce the morbidity and mortality associated with disseminated tumors.
Yang
Haiyan
H
Laboratory of Population Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Rouse
Jessica
J
Lukes
Luanne
L
Lancaster
Mindy
M
Veenstra
Timothy
T
Zhou
Ming
M
Shi
Ying
Y
Park
Yeong-Gwan
YG
Hunter
Kent
K
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D014408:Biomarkers, Tumor / Q000378:metabolism; D002110:Caffeine / Q000627:therapeutic use*; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
D000952:Antigens, Polyomavirus Transforming; D014408:Biomarkers, Tumor; D000697:Central Nervous System Stimulants; D002110:Caffeine