An Overview of the Molecular Biology of Lung Cancer

Lung cancer cells have defects in the regulatory circuits that
govern normal cell proliferation and homeostasis. Hanahan
and Weinberg 1 described the “hallmarks of cancer” as six
essential alterations in cell physiology that collectively dictate
malignant growth. These acquired capabilities found
in lung cancers are self-sufficiency of growth signals, insensitivity
to growth-inhibitory (antigrowth) signals, evasion
of programmed cell death (apoptosis), limitless replicative
potential, sustained angiogenesis, and tissue invasion and
metastasis. Transformation from a normal to malignant lung
cancer phenotype is thought to arise in a multistep fashion,
through a series of genetic and epigenetic alterations,
ultimately evolving into invasive cancer by clonal expansion.
2 These progressive pathological changes in the bronchial
epithelium—known as preneoplastic or premalignant
lesions—occur primarily as one of three distinct morphological
forms: squamous dysplasia, atypical adenomatous
hyperplasia, and diffuse idiopathic pulmonary neuroendocrine
cell hyperplasia. 3 Bronchial squamous dysplasia and
carcinoma in situ (CIS) are the recognized preneoplastic
lesions for squamous cell carcinoma; atypical adenomatous
hyperplasia (AAH), a putative preneoplastic lesion, for a
subset of adenocarcinomas; and neuroendocrine cell hyperplasia
for neuroendocrine lung carcinomas. 3 These preneoplastic
lesions, however, account for the development of only a
subset of lung cancers; for example, the precursor lesion for
the most common neuroendocrine carcinoma of the lung,
small cell lung carcinoma (SCLC), is unknown. Tumors
are believed to become increasingly malignant with time,
initiating tumorigenesis from possibly only a handful of
mutations followed by additional (and different) mutations
and epigenetic changes acquired during clonal expansion,
where cells possessing in vivo growth advantage become
dominant. 2
The identification and characterization of these molecular
changes in lung cancer is of fundamental importance for
improving the prevention, early detection, treatment, and
palliation of this disease. The overall goal is to translate these
findings to the clinic by using molecular alterations as (a)
biomarkers for early detection, (b) targets for prevention, (c)
tools for new molecular approaches, (d) signatures for personalizing
prognosis and therapy selection for each patient,
and (e) targets to specifically kill or inhibit the growth of
lung cancer in patients.
Lung cancer arises from neoplastic changes to epithelial
cells in the lung. However, it is not known whether all
lung epithelial cells are susceptible to malignant transformation
or only a subset of these cells; specifically, a major
question is whether the changes need to take place in lung
epithelial cells with stem cell–like properties. Lung cancer is
a heterogeneous disease clinically, biologically, histologically,
and molecularly. The underlying causes of this heterogeneity
are unknown and could reflect changes occurring in cells
with various potential for differentiation (e.g., squamous or
adenomatous) or represent different molecular changes occurring
in the same target lung epithelial cells. This heterogeneity
and molecular complexity contributes to the difficulty
in unraveling the pathogenesis of lung cancer. Multiple oncogenes,
tumor suppressor genes (TSGs), signaling pathway
components, and other cellular processes are involved in the
molecular pathogenesis of lung cancer. This chapter will review
molecular aberrations in lung cancer and the multiple
pathways through which it develops.
The two main disease categories of lung cancer, non–
small cell lung cancer (NSCLC) (representing 80% to 85%
of cases) and SCLC (representing 15% to 20%), are generally
classified based on differences in histological, clinical, and
neuroendocrine characteristics. NSCLC and SCLC can also
differ molecularly with many genetic alterations exhibiting
subtype specificity (summarized in Table 5.1). Additionally,
molecular studies of NSCLC have also revealed considerable
differences between the subtypes of NSCLC, particularly the
two most common subtypes: adenocarcinoma and squamous
cell carcinoma.