Non-small lung cancers (NSCLC) will be chemically induced at selected sites in dogs. These models result in canine NSCLC resembling human cancers and allows serial testing during neoplastic progression from normal epithelium to invasive lung cancer. Adjunctive to work with canine NSCLC, cancers from patients will be studied.
We aim to: 1) refine and standardize the new and not cost- effective subcutaneous bronchial autograft (SBA) model (14-15 SBAs/dog); 2) characterize the chromosomal changes found in NSCLC; 3) improve methods to determine patterns of altered DNA methylation, and delineate when changes in DNA methylation being during the neoplastic progression; 4) identify the stage when neoplastic transition in NSCLC becomes progressive without continued presence of carcinogen; 5) correlate chromosomal abnormalities, DNA methylation changes, histologic patterns, and biologic behavior of NSCLC in humans and in dogs; 6) explore genetically related factors associated with diversity of susceptibility to NSCLC carcinogenesis. Preneoplastic cell populations shall be serially harvested from SBAs and examined for changes in DNA methylation. Karyotyping tumors for humans and dogs will assess specific chromosomal abnormalities associated with the NSCLC polyploidy previously demonstrated in dogs and humans. Additional probes will be prepared and used to further evaluate DNA methylation patterns already shown to distinguish among varieties of human and of canine NSCLC. Correlation among patterns of DNA methylation, specific chromosomal alterations, histologic appearance, and biologic behavior of tumors will be sought regarding potential prognostic implications of specific DNA methylation patterns and/or cytogenic markers. Nude mouse transplants of NSCLC shall be used for cancer cell propagation and to study cytogenetic and DNA methylation correlates of tumor progression. After removing carcinogen from SBAs having specific preneoplastic changes, serial studies will provide data regarding dependence (or independence) of the NSCLC neoplastic progression upon continued presence of carcinogen. With assessment of DNA methylation patterns and karyotyping, the biologic and genetic differences between more and less carcinogen susceptible hosts will be explored. This project involves ongoing collaboration between surgeons, pathologists, cytogeneticists, and molecular biologists seeking a better understanding of NSCLC. It utilizes specimens from two species - humans and dogs, and proposes specifically to use the relevant canine model for investigations not possible in humans.

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National Cancer Institute (NCI)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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University of California Davis
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Ten Have-Opbroek, A A; Benfield, J R; Hammond, W G et al. (1994) In favour of an oncofoetal concept of bronchogenic carcinoma development. Histol Histopathol 9:375-84
TenHave-Opbroek, A A; Hammond, W G; Benfield, J R et al. (1993) Expression of alveolar type II cell markers in acinar adenocarcinomas and adenoid cystic carcinomas arising from segmental bronchi. A study in a heterotopic bronchogenic carcinoma model in dogs. Am J Pathol 142:1251-64
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