Consilience across evolving dysplasias affecting myeloid, cervical, esophageal, gastric and liver cells: common themes and emerging patterns.
In the present paper, an attempt is made to identify common biologic themes across dysplastic states affecting the marrow, gastro intestinal tissue, the cervix and liver as well as unifying patterns during disease evolution. The following algorithm appears generally applicable, although individual variations must necessarily be anticipated. It appears that there is an initial transforming event which in all dysplasias except that affecting the marrow has been found to be infectious. Increased cellular proliferation-increased apoptosis, telomere shortening, appearance of telomerase expression and clonal expansion follow the initial insult. Abnormalities in the cytokine environment are universally described and it is likely that the quintessential monoclonality aspect of dysplasia predisposes to accumulation of genetic mutations, and microsatellite instability leading to the appearance of evolved sub-clones. The conversion of a dysplastic phenotype to a malignant one reflects the success of one such sub-clone in developing a survival advantage over a large population of prematurely apoptotic neighbors. This state is usually acquired by silencing tumor suppressor genes through hypermethylation or actual loss or dysfunction. Thus, excessive apoptosis of cells resulting from a persistent infectious process predisposes the organ towards developing a cancerous phenotype. Evidence for the shared pathology is presented at length with the hope that these parallels between dysplastic states will be helpful in both biologic and therapeutic research.
Raza
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Pre-Leukemia and Leukemia Program, Rush Cancer Institute, Rush-Presbyterian, St. Luke's Medical Center, Chicago, IL 60612-3515, USA.
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002999:Clone Cells / Q000473:pathology; D003043:Cocarcinogenesis; D016207:Cytokines / Q000502:physiology; D019175:DNA Methylation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D009928:Organ Specificity; D019098:Telomerase / Q000096:biosynthesis / Q000502:physiology; D016615:Telomere / Q000648:ultrastructure; D014412:Tumor Virus Infections / Q000235:genetics / Q000473:pathology
D016207:Cytokines; D009363:Neoplasm Proteins; D019098:Telomerase