Introduction
1. tobacco consumption is believed to be responsible for > 90%
of lung cancers in men and
80 % in women
2. tobacco has been implicated in the development of esophageal
carcinoma acting
synergistically with ethanol consumption
3. since only a minority of smokers develop lung cancer implies
that there are other
genetic and enviromental factors
that contribute
4. epidemiologic studies have demonstrated familial risk
of lung cancer in some patients
who develop cancer at an earlier
age (<50 Yrs)
5. in the U.S., the incidence of esophageal adenocarcinoma has
risen faster than any other
cancer
a. tends to occur in young male patients with no history of tobacco
or ethanol abuse
b. chronic reflux, hiatal hernia, and Barretts esophagus are
thought to be predisposing
factors
c. Barretts esophagus increases the risk of developing esophageal
cancer 40-fold
Cell Cycle
1. cell proliferation normally proceeds in an orderly fashion
(GO,G1,S,G2 and M phases)
2. multiple regulatory proteins known as cyclins (A,B etc) are
involved in cell proliferation
3. 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
Dominant and Recessive Oncogenes
1. mutations associated with carcinogenesis may occur in dominant
or recessive (tumor
suppressor) genes
2. dominant oncogenes are genes in which mutation results in
constitutive growth stimulation
3. tumor suppressor genes tend to control cell proliferation
Growth Factors and Growth Factor Receptors
1. lung and esophageal cancers have been associated with abnormal
expression of a
variety of growth factors and
growth factor receptors
2. growth factors secreted by tumor cells may influence distant
cells (endocrine stimulation)
Gastrin-Releasing Peptide
1. 27 amino acid homolog of bombesin
2. GRP receptors are found on small cell cancer cells but are
absent on non-small cell cancer cells
3. in vitro proliferation of small cells can be inhibited by
antibombesin monoclonal
antibodies or antagonists
Epidermal Growth Factor Receptor
1. 170-kd tyrosine kinase glycoprotein
2. activaiton of EGFr ligand results in cell proliferation
3. overexpression of EGFr has been associated with 45% lung cancers
and 80% of esophageal cancers
4. EGFr overexpression in patients with non-small cell cancers
is associated with diminished survival
ErbB2/Neu
1. erbB2/neu gene encodes for a 185 kd transmembrane tyrosine
kinase receptor molecule
2. structurally related to EGF
3. present on normal ciliated epithelium, mucus cells, and type
II pneumocytes of the lung
4. overexpression had been associated with scca and adenoca
of the lung
Platelet-derived and Insulin-like Growth Factors and Their Respective
Receptors
1. both are important cell cycle progression in mammalian cells
2. PDGF, PDGFr expression have both been documented in
association lung and esophageal cancers
3. normal lung tissue does not express PDGF ligand, but lung
cancer cells do express PDGF
4. insulin growth factor ligands and receptors have been identified
in lung and esophageal cancer cell lines
5. 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
Cyclin D
1. the cyclin D gene appears to be amplified but not expressed
in ~ 10% of large cell and
squamous cell lung cancers
2. amplification and overexpression is seen in 32% of squamous
cell esophageal cancers
3. overexpression of cyclin D disrupts G1 cell cylce kinetics
resulting in damaged DNA and malignant transformation
RAS
1. 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
2. Ras mutations are among the most common oncogene defects in
human cancers
3. K-ras mutations are relatively common in pulmonary adenocarcinomas,
esp. in patients with a smoking history
Myc
1. family of genes which are expressed during mammalian development
and human
carniogenesis
2. 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
3. aberrant C-myc expression has been primarily documented in
small cell cancers
4. myc amplification occurs late in the process of carcinogenesis,
enhancing tumor
progression and metastasis
Tumor Suppressor Genes
3p
1. lung and esophageal cancers are associated with multiple genetic
alterations
2. the majority of these neoplasms are aneuploid
3. 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 |
