| Abstract |
Lung cancer, and in particular non-small-cell lung cancer (NSCLC),
remains the leading cause of cancer death throughout the world. The overall
five-year survival is less than 15%. Lung cancer mortality is higher than the
sum of mortality of breast, prostate and colon cancer together. Despite the
diagnostic improvements and the new therapeutic agents, in the last decades,
the percentage of the five-year survival has not been improved. Smoking
cessation remains the best method for prevention and reduction of disease
incidence.
Patients are usually symptomatic (94%) by the time of diagnosis. The
most common presenting symptoms are coughing, weight loss, dyspnea,
thoracic pain, and hemoptysis. Squamous cell carcinoma and adenocarcinoma
comprise the major histological subtypes.
The TNM staging system is currently in use for the disease staging.
There are three therapeutic approaches in use: surgery, radiotherapy and
combination chemotherapy. Third line chemotherapy with EGFR (epidermal
growth factor receptor) inhibitors is currently recommended in the advanced
disease or when patients do not respond to the second line chemotherapy.
However, in the future, novel targeted therapies could offer a wider range of
therapeutic options for lung cancer patients.
Recently, the progress on biology and genetics has contributed to a
better understanding of lung cancer pathogenesis, implicating that lung
cancer is the result of several genetic and epigenetic alterations. The latter are
due to chronic exposure to a variety of carcinogens that result in the
progressive transformation of a normal cell to neoplastic.
The multicellular organisms’ homeostasis substantially depends on the
proper presentation of a plethora of signals that cells are exposed to, during
their lifetime. Various soluble agents regulate the activation status of the
cellular receptors, connected via a complex signal transduction network,
which generates further signals regulating a certain biological response.
These cellular receptors include also the family of epidermal growth factor
tyrosine kinase receptors.
The epidermal growth factor receptor tyrosine kinase family consists of
four members: the EGFR/c-erbB-1, the HER2/c-erbB-2/c-neu, the HER3/cerbB-
3 and the HER4/c-erbB-4. All members of the EGFR family are
characterized by an articulate structure, which consists of an extracellular
component, where the ligand binds, a hydrophobic transmembrane
component and an intracellular component with tyrosine kinase activity. A
family of ligands, the EGF-related peptide growth factors, binds to the
extracellular domain of ErbB receptors leading to the formation of both homoand
heterodimers. Subsequently dimerization triggers the intrinsic tyrosine
kinase activity of the receptors and autophosphorylation of specific tyrosine
residues within the cytoplasmic domain. These phosphorylated residues
serve as docking sites for a variety of signal transducers (mediators), which
regulate the membrane to nucleus complex network of signal transmission,
leading to the modification of a biological response according to a certain
signal. The deregulation of this strictly controlled system due to protein
overexpression, or mutations of important components of this pathway, and
/or the autocrine stimulation through ectopic loops of growth factors, has
been correlated with the development of cancer.
There are extensive studies on the role of the EGFR family receptors in
the pathogenesis of NSCLC. The most studied receptors are the c-erbB-1
(EGFR) and the c-erbB-2 (HER-2 or c-neu). It has been supported that these
receptors are involved in lung cancer pathogenesis, development of
metastasis, resistance to treatment, and overall prognosis. However
contradictory results have also been reported. At present, targeted therapies
are clinically implemented against these receptors. Nevertheless, it remains
unknown who are the patients particularly prone to benefit from such a
treatment.
Based on the current literature, we embarked on an investigation of the
immunohistochemical expression of all four EGFR family members (EGFR, c138
erbB-2, c-erbB-3 and c-erbB-4) in paraffin blocks from 209 patients with
NSCLC. We also studied their co-expression, the expression of the potential
receptors pairs and we correlated our findings with patients’ demographic
parameters, tumor histological types, degree of differentiation, disease stage,
disease-free interval, and patients’ overall survival. Additionally, we
investigated whether the expression or the co-expression of the above
receptors represent an independent prognostic factor in NSCLC patients.
The study material consisted of 209 lung cancer tissue specimens, 129 of
which were obtained by open surgery. Five serial sections, 4-μm thick, were
cut from each, paraffin-embedded, lung tissue block. Four of the serial
sections of each patient were used for the immunohistochemical study. A
standardized quantification method was employed for the evaluation of the
results of immunostaining, for each one of the c-erbB receptors. Briefly, when
more than 10% of the cancer cells presented mild to moderate complete
membrane staining, the section was graded as weakly positive (2+), while
when more than 10% of the cancer cells presented intense complete
membrane staining, it was graded as strongly positive (3+). All the other
patterns of staining were considered negative (0 or 1+).
We detected overexpression of the receptors c-erbB-1, c-erbB-2, c-erbB-3
and c-erbB-4 in 47.7%, 23.7%, 6.5% and 25.2% of NSCLC patients,
respectively. Twenty-nine percent of all the samples studied were negative for
all the receptors of the c-erbB family, while only one of the receptors was
overexpressed in 43.7% of cases. The co- expression of two and three
receptors was 22.6% and 4%, respectively, while only one sample (0.5%)
expressed all four receptors.
The c-erbB-1 receptor was overexpressed in older patients, in squamous
cell carcinomas and in tumors with poor differentiation. The c-erbB-2 receptor
was overexpressed in adenocarcinomas and in poorly differentiated tumors.
The c-erbB-3 receptor was overexpressed mainly in poorly differentiated
tumors. The c-erbB-4 receptor was overexpressed in females and in patients
with advanced disease.
Considering the heterodimeric properties of c-erbB receptors and the
fact that different heterodimeric patterns may promote different biological
activities (activation of different biological pathways), we studied the protein
expression levels of the six potential receptor pairs. The c-erbB-1 and c-erbB-2
receptor pair was co-overexpressed in elderly patients. The c-erbB-1 and cerbB-
4 receptor pair was co-overexpressed in the female patients. For the cerbB-
1/c-erbB-3, c-erbB-2/c-erbB-3, c-erbB-2/c-erbB-4 and c-erbB-3/ c-erbB-4
receptor pairs no statistically significant correlations were found in regards to
age, sex, histological tumor type, differentiation or disease stage. The
overexpression of the c-erbB-1 receptor and the c-erbB-1/c-erbB-2 and c-erbB-
3/c-erbB-4 receptors pairs showed a statistically significant correlation with
the disease control rate. The overexpression of c-erbB-3 receptor and the cooverexpression
of c-erbB-1 and c-erbB-4 receptors showed a statistically
significant correlation with low median overall survival. The multivariate
analysis failed to reveal any independent statistically significant correlation
between the protein overexpression or co-overexpression of the c-erbB
receptors and overall survival.
The above findings suggest that the overexpression of a single receptor
or the co-overexpression of the receptors pairs correlate with certain
demographic parameters, disease control rate and disease outcome. Our
results also support the concept of developing and using small molecules to
inhibit the c-erbB receptors in carefully selected patients. The simultaneous
inhibition of more than one receptors may enhance the anti-neoplastic activity
of these agents.
Further studies on the expression of the c-erbB family heterodimers are
needed in order to develop predictive markers for the response to targeted
molecular therapies.
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