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Molecular Biology Of Lung Amp Esophageal Tumors

Molecular Biology

Molecular Biology of Lung and Esophageal Cancer

1. Introduction

A. tobacco consumption is believed to be responsible for > 90% of lung cancers in men and 80 % in women
B. tobacco has been implicated in the development of esophageal carcinoma acting synergistically with ethanol consumption
C. since only a minority of smokers develop lung cancer implies that there are other genetic and enviromental factors that contribute
D. epidemiologic studies have demonstrated familial risk of lung cancer in some patients who develop cancer at an earlier age (<50 Yrs)
E. in the U.S., the incidence of esophageal adenocarcinoma has risen faster than any other cancer
1) tends to occur in young male patients with no history of tobacco or ethanol abuse
2) chronic reflux, hiatal hernia, and Barrett’s esophagus are thought to be predisposing factors
3) Barrett’s esophagus increases the risk of developing esophageal cancer 40-fold

2. Cell Cycle

A. cell proliferation normally proceeds in an orderly fashion (GO,G1,S,G2 and M phases)
B. multiple regulatory proteins known as cyclins (A,B etc) are involved in cell proliferation
C. perturbation of cell cycle integrity due to alterations in various cyclin levels due to mutations involving oncogenes or tumor suppressor genes induces genomic instability, DNA amplification, and malignant transformation

3. Dominant and Recessive Oncogenes

A. mutations associated with carcinogenesis may occur in dominant or recessive (tumor suppressor) genes
B. dominant oncogenes are genes in which mutation results in constitutive growth stimulation
C. tumor suppressor genes tend to control cell proliferation

4. Growth Factors and Growth Factor Receptors

A. lung and esophageal cancers have been associated with abnormal expression of a

variety of growth factors and growth factor receptors

B. growth factors secreted by tumor cells may influence distant cells (endocrine stimulation)

5. Gastrin-Releasing Peptide

A. 27 amino acid homolog of bombesin
B. GRP receptors are found on small cell cancer cells but are absent on non-small cell cancer cells
C. in vitro proliferation of small cells can be inhibited by antibombesin monoclonal antibodies or antagonists

6. Epidermal Growth Factor Receptor

A. 170-kd tyrosine kinase glycoprotein
B. activaiton of EGFr ligand results in cell proliferation
C. overexpression of EGFr has been associated with 45% lung cancers and 80% of esophageal cancers
D. EGFr overexpression in patients with non-small cell cancers is associated with diminished survival

7. ErbB2/Neu

A. erbB2/neu gene encodes for a 185 kd transmembrane tyrosine kinase receptor molecule
B. structurally related to EGF
C. present on normal ciliated epithelium, mucus cells, and type II pneumocytes of the lung
D. overexpression had been associated with scca and adenoca of the lung

8. Platelet-derived and Insulin-like Growth Factors and Their Respective Receptors

A. both are important cell cycle progression in mammalian cells
B. PDGF, PDGFr expression have both been documented in association lung and esophageal cancers
C. normal lung tissue does not express PDGF ligand, but lung cancer cells do express PDGF
D. insulin growth factor ligands and receptors have been identified in lung and esophageal cancer cell lines
E. IGF-I,IGF-II or insulin stimulated mitogenesis in lung or esophageal cancer lines can be competitively inhibited by Mabs to the receptors or ligands

9. Cyclin D

A. the cyclin D gene appears to be amplified but not expressed in ~ 10% of large cell and squamous cell lung cancers
B. amplification and overexpression is seen in 32% of squamous cell esophageal cancers
C. overexpression of cyclin D disrupts G1 cell cylce kinetics resulting in damaged DNA and malignant transformation

10. RAS

A. H,K, and N-ras genes are members of a super gene family encoding for plasma

membrane proteins that are important in signal transduction from cell surface receptors invovled in mitogen-induced proliferation

B. Ras mutations are among the most common oncogene defects in human cancers
C. K-ras mutations are relatively common in pulmonary adenocarcinomas, esp. in patients with a smoking history

11. Myc

A. family of genes which are expressed during mammalian development and human carniogenesis
B. encode for DNA transcription factors that are critical for initiating movement of (G0) cells into and through the G1 phase of the cell cycle initiating DNA synthesis
C. aberrant C-myc expression has been primarily documented in small cell cancers
D. myc amplification occurs late in the process of carcinogenesis, enhancing tumor
progression and metastasis

12. Tumor Suppressor Genes

A. lung and esophageal cancers are associated with multiple genetic alterations
B. the majority of these neoplasms are aneuploid
C. deletions of 3p have been detected in nearly 100% of small cell lung cancers and >50% of non-small cell tumors and ~ 70% of esophageal cancers