Lung Cancer, Its Etiology Pathophysiology

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Lung Cancer, Its Etiology Pathophysiology

Lung cancer is a class of heterogeneous and multifactorial malignancies with diverse pathophysiological features. In terms of pathological characteristics, the small-cell lung carcinoma (SCLC), a subtype of lung cancer, is more common, accounting for 20% of the cases (Brugger et al., 2011). The progenitor stem cells for this carcinoma develop from a subset of bronchial and alveolar epithelial cells. The genetic/epigenetic alterations, largely attributed to tobacco smoke, alter signal transduction pathways in these cells leading to uncontrollable cell proliferation. This paper examines the etiologic factors and mechanisms of pathophysiology of lung cancer based on published research findings.

Genetic Alterations Associated with Lung Cancer

Two major histological types of lung cancer are identified: the small-cell lung carcinoma (SCLC) and the non-small-cell lung carcinoma (NSCLC). The two cancers have different precursor cells, involve separate pathophysiological pathways, and entail a dissimilar molecular basis (genetic aberrations). While mutations in the suppressor genes MYC, BCL2, c-KIT, and p53 cause SCLC, NSCLC is caused by mutations in p16, EGFR, and K-ras oncogenes (Timar, 2014, p. 142). Therefore, the pathophysiology of lung cancer is multifactorial.

The genes implicated, primarily Tp53, Rb, and E2F1, among others, encode for factors essential in cell proliferation and differentiation, apoptotic process, and angiogenesis (Nichols, Saunders, & Knollmann, 2012). The activation or repression of these genes causes all major lung cancer histological subtypes, i.e., SCLC, NSCLC, squamous cell carcinoma (SCC), and bronchioloalveolar carcinoma (BAC). Specifically, the repression of the Tp53 gene due to a missense mutation causes the malignant tissue to evade apoptosis, leading to lung cancer (Nichols et al., 2012). Tp53 gene is activated to repair damaged DNA via the apoptosis of progenitor cells. Therefore, the repression of this gene by tobacco smoke or viral protein inhibits the apoptosis of malignant cells, causing invasive growth.

The repression of the tumor-suppressor retinoblastoma (Rb) gene has also been implicated in most SCLC and NSCLC (McCance, Huether, Brashers, & Rote, 2009). The Rb-regulation pathway is repressed through the modification of the protein caused by genetic aberrations (Nichols et al., 2012). Rb-protein repression can also arise from the inactivation of upstream sequences (P16/Ink4 gene) or deletions in the Rb sequence (Nichols et al., 2012). The protein regulates the cell cycle process. According to Sequist and Lynch (2011), the inactivated version of the protein produces TFs essential in the transcription of factors required in cell progression, differentiation, and survival (p. 431). Therefore, diminished Rb activity caused by Rb protein modifications (deletions) leads to lung cancer.

The Rb protein has also been shown to trigger apoptotic cell death (Sequist & Lynch, 2011). Therefore, Rb inactivation inhibits the apoptosis of malignant cells, leading to carcinogenesis. Besides Rb and Tp53 repression, loss of heterozygosity (LOH) in 3p has been implicated in most lung cancer subtypes (McCance et al., 2009, p. 175). Several putative tumor-suppressor genes occupy the 3p sequence. Genetic alteration inactivates these genes leading to carcinogenesis.

Pathophysiology of Specific Lung Cancer Types

Small-cell Lung Carcinoma

SCLC is the most prevalent histological type of lung cancer. Tp53 and Rb gene repression occurs in most SCLC patients. Also, SCLC is associated with the up-regulation of E2Fs (transcription factors) and Myc genes that amplify cell proliferation (Sequist & Lynch, 2011). The inactivation of Tp53 and Rb in bronchial and alveolar epithelial cells was shown to inhibit the apoptotic signal pathways in mice models, leading to the unhindered development of metastatic neoplasm cells (Yamaguchi, Kugawa, Tateno, Kokubu, & Fukuchi, 2012). The cells developed following the NE lineage and expressed the NE markers.

In this study, heterozygous Rb and Tp53 gene loss caused SCLC, but tumor development was slower than in homozygous deletions (Yamaguchi et al., 2012). Thus, Rb and Tp53 inactivation is important in the NE lineage and SCLC development. The inactivation and epigenetic silencing of these two genes cause metastatic cells to evade apoptosis, leading to lung cancer.

Adenocarcinoma (ADC)

Lung ADC affects lung periphery tissues. The K-ras gene mutation is the primary cause, occurring in over 30% of lung ADC cases (Timar, 2014). However, Tp53 gene suppression is more common in advanced ADC, particularly in bronchioloalveolar carcinomas. Also, mutations in the epidermal growth factor receptor (EGFR) gene have been found in up to 50% of lung adenocarcinoma cases (Brugger et al., 2011). The K-ras mutations were absent in cases where EGFR gene alterations were implicated, implying that the two mutations are mutually exclusive.

EGFR mutations occur in most AAH lesions that develop into lung ADC. Brugger et al. (2011) found that several lesions and EGFR mutations rises as the adenocarcinoma advances. Thus, the EGFR gene aberrations play a crucial role in the initiation and progression of adenocarcinoma of the lungs compared to K-ras mutations. Further, the dysfunction of the EGFR signaling pathway activates various factors essential for the initiation of ADC in precursor cells. The Clara cell divides to repair damaged alveolar epithelial (Brugger et al., 2011). Therefore, EGFR mutations cause uncontrolled proliferation of the Clara cells, leading to ADC initiation.

Squamous Cell Carcinoma (SCC)

The occurrence of lung SCC correlates with the over-expression of EGFR protein. However, K-ras gene mutations, which are common in most ADC cases, do not occur in SCC (Yan, Witsuba, Emmert-Buck, & Erickson, 2011). Further, the activation of the PIK3CA gene, which occurs downstream of the EGFR region, has been found in up to 50% of the squamous cell carcinoma cases (Yan et al., 2011). Thus, the PIK3CA gene activation occurs through the EGFR signaling pathway and correlates with tobacco smoking. Unlike in ADC and SCLC, Tp53 gene repression is rare in SCC. The risk of SCC increases when the Rb pathway is inactivated through p16/Ink4 silencing (Yan et al., 2011).

Large Cell Carcinoma (LCC)

The precursor cells of this histological type of lung cancer are the undifferentiated NSCLC, ADC, and SCC carcinomas. LCC accounts for only 10% of the carcinomas of the lung (Li et al., 2014). While precursor lesions for LCC have not been detected, it presents molecular alteration similar to those found in the ADC (Li et al., 2014). A subtype of LCC, i.e., LCNEC, contains NE markers similar to those in SCLC. Further, the repression of Rb and Tp53 genes seen in other carcinomas occurs in LCNEC.

Pathogenesis of Lung Cancer

Lung cancer development is linked to carcinogen-induced mutations. Cigarette smoke is a significant risk factor in the initiation and growth of carcinomas. Lung cancer initiation primarily involves 3p deletions and p53 mutations (Steliga & Dresler, 2011, p. 611). Lung epithelium develops initiated cancer cells due to exposure to cigarette smoke. The smoke not only irritates the epithelium, but it also contains nicotine, a known carcinogen. Cancer initiation requires over 20 years of continuous exposure to cigarette smoke.

Cigarette smoke primarily activates the EGFR signaling pathway, which marks the beginning of SCLC initiation. Besides the EGFR pathway, carcinogenic agents in the smoke could also alter the p16/INK4, cyclinD1, and Rb pathways. The expression of the EGFR gene has been shown to induce ADC in the absence of K-ras mutations (Guo, Tosun, & Horn, 2011). Further, EGFR or K-ras gene stimulation activates the EGFR-ras-RAF-MAPK signal transduction, leading to lung ADC initiation (Guo et al., 2011, p. 388). Therefore, it seems that K-ras gene alterations complement EGFR stimulation to initiate the disease.

Another gene implicated in the EGFR signaling pathway is PIK3CA that occurs downstream of the EGFR gene. PIK3CA stimulation occurs in most SCC cases, demonstrating its role in the EGFR pathway. Similarly, the EGFR gene is over-expressed in SCC cases, indicating that it has a role in EGFR pathway activation (Brugger et al., 2011). Therapies focus on inhibiting EGFR gene alterations to disrupt the signaling pathway that induces alveolar SC activity. ADC treatment involves tyrosine kinase inhibitors that target genes implicated in the pathway (Brugger et al., 2011).

Normal cells overcome carcinogenic stresses through suppressor genes. An example of such genes is the Tp53 gene, which encodes for a protein that stimulates cell cycle arrest and apoptotic damage of irreparable DNA (Sequist & Lynch, 2011). Therefore, the inhibition of these preventive processes by carcinogens can initiate uncontrolled neoplastic cell proliferation. The cells evade the growth-regulating system when genetic alterations suppress the Tp53 gene. Further, epigenetic effects on the suppressor genes inactivate them, contributing to carcinogenesis. Therefore, the repression of suppressor genes plays a role in the evasion of apoptotic damage of irreparable mutations, leading to lung cancer. On the other hand, the activating mutations in K-ras and P13KCA genes due to carcinogenic agents in smoke stimulate carcinogenesis (Sequist & Lynch, 2011, p. 438).

Conclusion

The heterogeneous nature of lung cancer could be attributed to diverse pathophysiological processes and multifactorial genes. The activation of the EGFR signaling pathway and associated genes represses apoptotic removal of damaged DNA, leading to the accumulation of mutations that cause NSCLC cancers. Also, mutations involving the K-ras gene due to cigarette smoke induces ADC initiation and development. In contrast, the etiology of SCLC is associated with mutation-related suppression of Tp53 and Rb activity.

References

Brugger, W., Triller, N., Blasinska-Morawiec, M., Curescu, S., Sakalauskas, R., Manikhas, G.,&Cappuzzo, F. (2011). Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. Journal of Clinical Oncology, 29(31), 4113-4120.

Guo, N., Tosun, K., & Horn, K. (2011). Impact and interactions between smoking and traditional prognostic factors in lung cancer progression. Lung Cancer, 66(3), 386392.

Li, J., Hu, Y., Wang, Y., Tand, X., Shi, W., & Du, J. (2014). Gene mutation analysis in non-small cell lung cancer patients using bronchoalveolar lavage fluid and tumor tissue as diagnostic markers. International Journal of Biological Markers, 29(4), 328-336.

McCance, K., Huether, S., Brashers, V., & Rote, N. (2009). Pathophysiology: The biological basis for disease in adults and children. Maryland Heights: Mosby.

Nichols, L., Saunders, R., & Knollmann, F. (2012). Causes of death of patients with lung cancer. Archives of Pathology & Laboratory Medicine, 136, 1552-1558.

Sequist, L., & Lynch, T. (2011). EGFR tyrosine kinase inhibitors in lung cancer: An evolving story. Annual Review of Medicine, 59, 429-442.

Steliga, M., & Dresler, C. (2011). Epidemiology of lung cancer: Smoking, secondhand smoke, and genetics. Surgical Oncology Clinics of North America, 20(4), 605-618.

Timar, J. (2014). The clinical relevance of KRAS gene mutation in non-small-cell lung cancer. Current Opinion in Oncology, 26(2), 138-144.

Yamaguchi, F., Kugawa, S., Tateno, H., Kokubu, F., & Fukuchi, K. (2012). Analysis of EGFR, KRAS and P53 mutations in lung cancer using cells in the curette lavage fluid obtained by bronchoscopy. Lung Cancer, 78(3), 201-206.

Yan, W., Witsuba, I., Emmert-Buck, M., & Erickson, H. (2011). Squamous cell carcinoma similarities and differences among anatomical sites. American Journal of Cancer Research, 1(3), 275-300.

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