Our promise to you:
Guaranteed product quality, expert customer support.
Lung cancer is the second most common cancer in men and women, and it is the leading cause of cancer-related death in the USA. Small cell lung cancer (SCLC) represents 13% of all newly diagnosed cases of lung cancer worldwide, or over 180 000 cases every year. More than 90% of patients with SCLC are elderly current or past heavy smokers, and risk rises with increasing duration and intensity of smoking. Although rare cases have been reported in people who have never smoked, SCLC, by contrast with non-small cell lung cancer (NSCLC), is not associated with a specific somatic mutation.
Cytogenetically, SCLC has several distinguishing abnormalities in DNA copy number. Several important genetic and molecular characteristics have been recorded, including the identification of autocrine growth loops, proto-oncogene activation, and loss or inactivation of tumor-suppressor genes. The deletion 3p(14–23) in the region containing the tumor-suppressor gene FHIT is seen in virtually all SCLC tumors. Another common finding is a copy-number gain in 7p22.3, which encompasses MAD1L1, which encodes the mitotic spindle assembly checkpoint protein MAD1. Nearly all patients with SCLC also have a loss of the tumor-suppressor retinoblastoma gene RB1 and have more frequent mutations in TP53 than do patients with NSCLC. These mutations decrease proapoptotic activity during SCLC tumorigenesis, which encourages aggressive growth and increases the survival advantage of carcinogenic cells. Tyrosine kinase signaling genes, including EGFR and KRAS, are rarely mutated.
SCLC cells are surrounded by an extensive extracellular matrix that includes tenascin, collagen IV, fibronectin, and laminin. High expression of these components is associated with a poor prognosis. Adhesion of SCLC cells to the extracellular matrix requires β1-integrins and leads to suppression of chemotherapy-induced apoptosis by stimulation of PI3K. The cell cycle arrest and apoptosis normally induced by etoposide are, therefore, prevented. Several growth factors have been implicated as mediators of autocrine signaling in SCLC, including growth hormone releasing hormone (GHRH), insulin-like growth factor I (IGF-I), bombesin, hepatocyte growth factor (HGF), and fibroblast growth factor 2 (FGF2). Inhibitors of several of these growth factor pathways are in clinical development. In addition, targeting of the mitochondrial apoptosis pathway is currently being explored as a therapeutic strategy for SCLC. FGF2 drives the proliferation of SCLC cells, and confers resistance to etoposide in vitro by upregulation of antiapoptotic proteins (Bcl-XL, Bcl-2, and X-linked IAP) and suppression of the proapoptotic protein BAD. This activity depends on the mitogen-activated protein kinase pathway in a regulatory protein complex comprising RAF, protein kinase C ε type, and S6K. Inhibition of FGF2 signaling by the compound PD173074 impairs SCLC proliferation and chemo resistance, and induces apoptosis in vivo and in vitro.
Currently, a series of signaling pathways have been identified that might yield new drug targets. Creative Biogene, as a leading biotechnology company, is able to offer various SCLC pathway related products including stable cell lines, viral particles and clones for your drug discovery projects.