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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA026529-11S1
Application #
3167346
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1988-02-01
Project End
1992-11-30
Budget Start
1990-02-01
Budget End
1992-11-30
Support Year
11
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
Schools of Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
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
Benfield, J R; Hammond, W G (1992) Bronchial and pulmonary carcinogenesis at focal sites in dogs and hamsters. Cancer Res 52:2687s-2693s
Hammond, W G; Benfield, J R; Teplitz, R L (1991) Metastatic behaviour of canine lung carcinoma in autochthonous and xenotransplant hosts. Clin Exp Metastasis 9:567-77
Hammond, W G; Teplitz, R L; Benfield, J R (1991) Variable regression of experimental bronchial preneoplasia during carcinogenesis. J Thorac Cardiovasc Surg 101:800-6
Hammond, W G; Benfield, J R; Teplitz, R L (1991) Metastases from fresh human non-small cell lung cancers propagated in nude mice. Cancer Lett 61:53-60
Ten Have-Opbroek, A A; Hammond, W G; Benfield, J R (1990) Bronchiolo-alveolar regions in adenocarcinoma arising from canine segmental bronchus. Cancer Lett 55:177-82
Hammond, W G; Yellin, A; Gabriel, A et al. (1990) Quantitative DNA alterations during 5-azacytidine-induced differential modulation of benzo(a)pyrene carcinogenesis in hamster bronchi. Cancer Commun 2:135-44
Hammond, W G; Yellin, A; Gabriel, A et al. (1990) Effects of 5-azacytidine in Syrian golden hamsters: toxicity, tumorigenicity, and differential modulation of bronchial carcinogenesis. Exp Mol Pathol 53:34-51
Derrick, M J; Hammond, W G; Pak, H Y et al. (1988) Non-small cell lung cancer in autogenous subcutaneous bronchial grafts in dogs. J Thorac Cardiovasc Surg 95:562-71

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