Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that aberrant induction of COX-2 and up-regulation of the
prostaglandin cascade play a significant role in
carcinogenesis, and reciprocally, blockade of the process has strong potential for
cancer prevention and
therapy. Supporting evidence includes the following: [1] expression of constitutive COX-2-catalyzed
prostaglandin biosynthesis is induced by most
cancer-causing agents including tobacco
smoke and its components (polycylic aromatic
amines, heterocyclic
amines,
nitrosamines), essential
polyunsaturated fatty acids (unconjugated
linoleic acid),
mitogens,
growth factors, proinflammatory
cytokines, microbial agents,
tumor promoters, and other epigenetic factors, [2] COX-2 expression is a characteristic feature of all premalignant
neoplasms, [3] COX-2 expression is a characteristic feature of all
malignant neoplasms, and expression intensifies with stage at detection and
cancer progression and
metastasis, [4] all essential features of
carcinogenesis (mutagenesis, mitogenesis, angiogenesis, reduced apoptosis,
metastasis, and immunosuppression) are linked to COX-2-driven
prostaglandin (PGE-2) biosynthesis, [5] animal studies show that COX-2 up-regulation (in the absence of genetic mutations) is sufficient to stimulate the transformation of normal cells to invasive
cancer and metastatic disease, [6] non-selective
COX-2 inhibitors, such as
aspirin and
ibuprofen, reduce the risk of human
cancer and precancerous lesions, and [7] selective
COX-2 inhibitors, such as
celecoxib, reduce the risk of human
cancer and precancerous lesions at all anatomic sites thus far investigated. Results confirming that COX-2 blockade is effective for both
cancer prevention and
therapy have been tempered by observations that some
COX2 inhibitors pose a risk to the cardiovascular system, and more studies are needed in order to determine if certain of these drugs can be taken at dosages that prevent
cancer without increasing cardiovascular risk. It is emphasized that the "inflammogenesis model of
cancer" is not mutually exclusive and may in fact be synergistic with the accumulation of somatic mutations in tumor suppressor genes and oncogenes or epigenetic factors in the development of
cancer.