The lung cancer is of primary concern among western population in the western world by virtue of exaggerated rate of smoker compared to non smokers. The pathology of lung cancer comprises of genomic instability resulting in abnormalities over a long span. The variations occur at gene level via process called as gene silencing mediated methylation; amplification of DNA, sequence changes in DNA along with looses and gains of whole chromosome. The genetic alterations observed in cell lung cancer contain a loss of regions which are in turn part of the genome especially chromosomes 9p and 3p and it is also observed that there is a deletion in the chromosomal arm in 5p and recognizable mutations were identified in K-ras and p53.( Thibervillie et al., 1995)
k-ras mutations were identified in almost all the cases of adenocarcinomas of the lung tissue.p53 is a predominant suppressor gene for tumors and can be used to examine spectrum of the cancer causing mutations. These mutations are observed in small cell carcinomas and squamous carcinomas. The p53 mutations are observed in two thirds of the cancers of lung. The critical candidate for the Rb pathway is the tumor suppressor gene termed as p16 which is activated in more than 40% of NSCLS’s. (Hitoshi Kitamura et al., 2008)
The inherited genes are the primary factors for generating cancers such as lung cancer. The difference between SCLC and NSCLC is critical in clinical studies of lung cancer. The small cell lung disease is a tumor of bronchus (Barnard.,1926). The Rb function plays a crucial part in initiating carcinogenesis especially in small cell lung carcinoma cyclin dependent kinases are hyperphosphorylated. The inactivation of Rb protein occurs and E2Fs are released. The Cdks activity is controlled by the p16/Ink4 which are upstream factors along with the cyclin D1. The E2Fs which were set free transactivates the genes which are involved in progression of cell cycle and intervenes Tp53 dependent apoptosis. It is also observed that increments in free E2Fs as a result of protein loss are not uncommon in SCLC. The anti apoptotic pathway is initiated with the over expression of Bcl-2. (Hitoshi Kitamura et al., 2008)
The role of EGFR signaling pathway (Hitoshi Kitamura et al., 2008)
The activation of the EFGR signaling pathway plays a vital role in NSCLC enhancement. It is observed that the cell has a potential to avoid itself from neoplastic transformations as a response to stresses incurred due to oncogenes.
Hishoto kitamura et al., 2008)
The hypothesis recently proposed suggests that the basis for tumor generation lies in an epigenetic disruption which is polyclonal in nature and of stem or progenitor cells. These are mediated by tumor inducing genes. The epigenetic change observed is due to the permethylation and hypomethylation of the key genes and imprinting loss. Most of the cancers are not original clonally but among the heterogeneous populations.Tp53 and Rb genes are constitutionally and intrinsically inactivated via mutations and the gene inactivation in case of SCLC. In case of NSCLC, the Rb pathway is discarded due to the inactivation of the multiple regulators which are upstream (Hishoto et al., 2008). The activation of EGFR signaling is a key and preliminary stage in NSCLC. Identifiable pleiotropic effects were observed on several types of cell due to TGF beta. The promotion of the tumor and its inhibition along with homeostasis of the cell is essential. The anti proliferative activities should be avoided by the tumors and hence regulating cell mediated immunity and angiogenesis. The receptors of the epidermal growth factor families are the kind of tyrosine kinase receptors which are transmembrane. They induce enhanced resistance to radiotherapy and chemotherapy. The downstream signaling activity is linked with HER2 dimers. HER3 doesn’t contain kinase activity. The macrophages which are infected will release epiregulin and it binds to HER4 and EGFR. In case of NSCLC, HER4 is over expressed and related with metastasis of the lymph node which generally observed in the primary stages of the disease. The consortium of ERK/MEK/RAF/RAS pathway controls cellular responses at cellular level to the growth factor receptors and growth factors, and it’s also observed that these are up regulated in several cancers. The tyrosine kinase and lipid kinase links with PTEN/AKT/PI-3K and is a crucial in regulating treatment failure, metastasis and cancer growth. In case of SCLC and NSCLC cell lines, PI-3K is activated. The tumor suppressor gene like tensin and phosphatase homologue is deleted on chromosome 10 and is a negative regulator of AKT and PI-3K. In lung cancers, the PTEN proteins are expressed and it activates AKT pathway. The SCLC is involved in secreting vasoactive peptides and hormones like vasopressin and gastrin releasing peptides. SCLC cells attach to the extra cellular proteins and are involved in stimulation of beta 1 integrin kinase activation which is mediated by pI3. A linkage analysis supports that 6q23 to 25 is a specified locus in lung cancer which is inherited (Alison C Mackinnon et al., 2010).
MET is a kind of receptor for tyrosine kinase and the ligand is the hepatocytes growth factor and it is involved in metastasis and invasion along with cell proliferation. The PI3K-AKT and mTOR pathway is one of the signaling pathways which are linked with anti apoptosis. The concept called as mutant allele specific imbalance is a novel form of oncogene activation. The recognizable regression of the marked tumor with relation to EFGR-TKI is observed in lung cancers which inturn is due to the mutation of EGFR and it depends on EGFR kinases activity. There is a link between non coding small RNA and tumors. The micro RNAs or mi RNA belongs to a group of non coding small RNAs which are involved in regulating mRNAs by the repression during post transcription stages. mi RNAs are altered in NSCLCs have been observed in many cases. The miR-34 which is a tumor suppressor gene is identified as the p53 targets. This is capable of inducing the senescence, apoptosis and cell cycle arrest. miR 34b/c is observed to be down regulated and the induction of miR 34b/c is involved in suppressing the cell proliferation of NSCLC cell lines. The cluster of miR-17-12 is located at 13q31.3 which is found to be over expressed and drastically amplified in case of lung cancer in SCLCs. It is also observed that the cluster of polycistronic miRNA -17-92 is identified to be involved in promotion of angiogenesis of tumors in paracrine fashion. Recent past, there has been a debate of stem cells which have capability of pluripotency and self renewal which can act as source of cancer cells. The key pathways such as Wnt pathway, Hedgehog pathway and notch pathway are reported in case of lung cancers ( Shinichi Toyooka et al., 2011).
Hitoshi Kitamura, Takuya Yazawa, Molecular and genetic pathogenesis of lung cancer, differences between small cell and non small cell carcinomas, The open pathology Journal, 2008, 106-114
Aldinucci D, Perris R. Cell origin of tumors and the persistence of cancer propagating cells in tumor lesions. Open Pathology J 2008; 2: 6- 12
Nuciforo P, Fraggetta F. Cancer stem cell theory: pathologists’ considerations and ruminations about wasting time and wrong evaluations. J Clin Pathol 2004; 57: 782-3.
Shinichi Toyooka, Molecular oncology of lung cancer. Gen thorac cardiovasc surg,2011, 59: 527-537