Dr S.T. Sathya Meonah Phd.,
Small cell Lung Cancer is one of the predominant and stubborn neoplasms of our time. In my previous article (A Basic Overview of Small Cell Lung Cancer), I have briefed about the disease and other prime factors that influence its growth. Here, in this blog post, I will throw light upon the diverse genetic and molecular markers that assist in the pathogenesis.
Generally, molecular and genetic studies are arduous to understand and I know it practically (there were days when I spent many hours swotting with my genetic books without understanding a piece 😉). But I bet molecular studies are really fascinating.
Oncogenes – origin and growth
The molecular and pathological anomalies that takes place during the development of neoplasms are still scientifically explored. Since the normal pulmonary cells express varied growth factors and regulatory peptides, the neoplasm of lung cells is expressed as a complex loop involving autocrine and paracrine growth stimulatory oncogenes.
Thousands of gene representing probes are contained in cDNA and oligonucleotide microarrays.
Bombesin autocrine loop
The genetic marker Gastrin releasing peptide (GRP) from the amphibian peptide bombesin containing the 27-amino acid mammalian homologue expresses itself as oncogene.
Immunohistochemical analysis on SCLC has revealed that the ligand portion of the autocrine loop GRP/BN and the three receptors of GRP/BN are expressed oncologically.
No genetic modifications affecting the genes encoding the components of the pathway has been identified. Hence the reactivation mechanism of these regulatory loops is not clearly studied. Studies with drugs which interfere with the expression of these autocrine loops in pre-clinical studies are underway.
Tyrosine autocrine loops
The neuroregulins and their receptors, the transmembrane receptor tyrosine kinases belonging to the ERBB family, the KIT proto-oncogene coding tyrosine kinase receptor – CD117 with its ligand and stem cell factor makeup a potential growth stimulatory loop in SCLC.
Similarly, insulin like growth factor 1 and 2, type I insulin like growth factor receptor are also expressed in SCLC. This pathway provides potential therapeutic markers through tyrosine kinase inhibitors and KIT blockage.
Other significant oncogenes arising from growth stimulators include MYC family genes that express in SCLC like MYC, MYCN and MYCL. Amplification of these genes lead to protein overexpression in SCLC and serve as a genetic marker.
Recurrent SCLC patient tumour cell lines after chemo therapy treatment express MYC amplification compared to primary tumours.
One the earliest studies on MYC DNA amplification was conducted by Johnson et al., in 1996 who identified about 126 tumour cell lines form SCLC patients. Other researchers also reported that MYC family DNA amplification is the commonly occurring tumour types among recurrent SCLC patients previously treated by chemotherapy and greatly affect the survival rate.
Krystal (1988) reported that transcriptional dysregulation leads to overexpression of mRNA c-myc and L-myc leading to protein overexpression.
Intrusion in programmed cell death
Tumour cells escape pathways leading to apoptosis unlike normal cells. BCL-2 proto-oncogene product and TP53 tumour suppressor gene product is responsible for apoptotic chain activities in the cell. BCL-2 acts as apoptotic inhibitor primarily in SCLC than NSCLC.
Many researchers have reported that positive bcl-2 expression is associated with neuroendocrine differentiation in lung cancers. Overexpression of the gene have been related to good prognosis and high survival rate. But contrary to this finding,
Maitra et al., has reported that bcl-2 has no influence upon survival after chemotherapy. These controversies reveal that bcl-2 has a more complex operation with other genetic factors like p53, ras and myc etc. The expression of BCL-2 and its role in chemotherapy in SCLC or survival has to be scientifically explored.
Oncogenes are the modern genetic markers that gauge the severity of the neoplasm and assist in disease prognosis. These markers though complicated play a very special role in diagnosis and treatment especially after chemotherapy.