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5.11 The Carcinogenic Process in a Smoker

A gradual process of damage to lung tissue creates a tumor. Let us look at the development and spread of squamous cell lung cancer in a smoker:

1. Columnar Cells Protect the Lung. Tall columnar cells lining the air passages help keep the lungs clean and secrete sticky mucus which coats the entire respirator tract with a protective barrier. This mucus traps dust particles and cilia sweep the mucus and trapped dirt out of the lungs and throat, through a cough. Cells signal other cells to grow when damage occurs, and the body maintains an orderly system of cellular repair and cellular death.

2. Irritation to Columnar Cells. Poisons in cigarette smoke damage the cilia and the sweeping motion slows. Irritation to columnar cells results. In response to this irritation, the lung tissue produces additional mucus. The damage prompts signals for increased production. A wholesale alteration of cell production and signaling is beginning.

3. Columnar Cells Deteriorate and Metaplasia Develops Irritation from smoking continues, and columnar cells deteriorate and change shape. Cilia disappear and columnar cells transform themselves into flat, lacelike cells, a process called metaplasia. Various growth factors are activated, and tumor suppresor genes, the bodyís monitors are beginning to malfunction. If tissue were analyzed, DNA damage at least three chromosome locations 3p14, 9p21, and 17p13 would likely be seen.

4. The Precancerous Phase Called Dysphasia These metaplastic cells become increasing abnormal until they reach a precancerous stage called dysplasia. Considerable changes have now taken place over 10-15 years changing normal tissue to precancerous ones. A number of growth factors signaling tumor replication and related functions have been activated, and the bodyís system of cell repair and orderly cell death (apoptosis) has been damaged.

However, these changes will not impact any bodily function, or be apparent on an x-ray, standard blood test, or physical examination. For squamous cell cancer, these changes will be apparent on a sputum cytology test, where the sputum and cells from a deep cough are analyzed. Smoking cessation may allow some of this cellular damage to be repaired and restored, though former smokers will always have an increased risk of lung cancer.

5. Tumor Development A small growth or tumor develops, partly as a result of the bodyís attempt to repair damaged tissue. Assuming the tumor is non-small cell the most common, we now have a stage 1 non-small cell lung tumor. If the tumor is surgically removed at this stage, the patient will have an excellent 5 year prognosis. If is small and less than a centimeter, the tumor can probably be seen only on a chest Ct scan. If it is a little larger, it may be visible on an x-ray.

The tumor still will probably not impact normal functions or cause pain or discomfort In Japan, many lung tumors are detected at this stage through screening. Since no screening program exists in the U.S., most tumors here will be diagnosed later.


6. Lymph Node Involvement Mirroring the process of wound repair, the new cells create sources of blood supply, enabling the tumor cells to migrate to other parts of the body. Cancer cells come into nearby lymph nodes and spread both through lymph nodes and blood vessels. Anti-angiogenic drugs may in the future inhibit this process. Depending upon the location of the affected lymph nodes, the cancer will now be stage 2 or 3. Impacting breathing or causing pain, the tumor may cause some discomfort prompting a medical visit where it can be diagnosed.

7. Metastasis The tumor travels from a lymph node to another organ. Complex proteins manage to break down protective barriers in the basement membrane of other tissue enabling the cancer cells to penetrate. Surgery is not an option given the widespread nature of the cancer. Chemotherapy will be prescribed to inhibit the process of cell reproduction, lengthen life and reduce some symptoms. Since chemotherapy impacts normal cells, the extent must be limited. Newer forms of gene therapy will be prescribed to stop the aberrant cell signaling and inhibit certain growth factors. See Lungcheck (8).

Parts of this process may vary: tumors may take from 15 to 50 years to develop, non-smokers may contract cancer through seemingly different processes, lymph nodes may not always be cancerous, progression of the tumor can vary, and the location of cellular damage will also vary. Scientists have difficulty understanding which cellular changes come first, what is the order of cause and effect, which cellular abnormalities are the most important ones, which cells if repaired would impact cure or frustrate metastasis. Studies show 50 or 60% of cancer patients have a given cell abnormality, and determining which gene malfunctions cause the tumor remains problematic. Here are the major genes associated with lung cancer.




Tumor Supressor Gene P-53 disruptions are identified in many cancers including lung. P-53 helps repair damaged cells and activate processes of cell death when repair is impossible.

While effective in laboratory tests on cells, P-53 treatment has not been proven in clinical trials.

RB Retinoblastoma

Tumor Supressor Gene

Associated with small cell lung cancer.

None to date

Epidermal Growth Factor









Erb 2

Gene and receptor associated with creation and spread of lung tumors






Part of the Egf family,

with some clinical trials showing a role in various cancers.

Iressa has been FDA approved for treatment after chemotherapy. Other drugs like , Tarceva are showing initial success. Trials combining the drugs with chemotherapy have been disappointing.

Herceptin successfully used for breast cancer, significance in lung cancer unclear.

Vascular Endothelial Growth Factor

Associated with angiogenesis

Drugs targeting VEGF and receptors make logical sense, but remain unproven in clinical trials. Avastin and Neovastat, conflicting results. See (17)

Cox 2

Produce in response to various types of inflammation

Celebrex promising in cell studies. Cox-2 inhibitors showing success with various types of cancers and other diseases.


Cells have limited number of replications. This substance enables tumors to continually replicate

Drugs makes logical sense but remain unproven. Rhodacyanine (MKT077) and FJ5002

address teleromerase but there is little information about these drugs.


Production of MMPís enables basement matrix of organs to be penetrated and cancer cells to enter.

Marimastat trials disappointing

Cyclin D

Cyclin D1 gene is located on chromosome 11q13. This chromosomal region is amplified in a wide variety of human cancers . Associated with RB, production helps cells proceed through cycle

Flovopirodol (Aventis) decrease of cyclin D1 by repressing the cyclin D1 promoter


Helps prevents apoptosis (cell death).

Scientists are assessing whether levels of BCL-2 can be used as a tumor marker.

5.20 The Readerís Role

Many readers will want as much information as possible about the science behind lung cancer and the drugs that will be prescribed. Others will not and would prefer to simply review the types of drugs customarily prescribed. You may go to later chapters to read about specific drugs, or as I would recommend, try to get a basic understanding of the underlying science.

5.21 Multiple Changes

Multiple genetic changes appear needed to create a lung tumor, though a small number of changes can create other types of cancer. For example, a single change in one gene is associated with a particular type of leukemia. We know that multiple changes are needed in lung cancer.

In one way, that is a blessing. It explains why exposure to a carcinogen such as smoke does not immediately cause a tumor and even multiple changes may not be sufficient. The need for considerable genetic change explains why it takes many years for a smoker to contract cancer and why some may never get it. Once those multiple changes do occur, it is difficult to undo a system of signaling which has undergone considerable disruption. Indeed, the most effective treatment remains removal of the tumor, not attempts to correct the existing disease.

5.22 Gene Repair and Apoptosis

Lung cancer involves damage to various genes and a failure of the bodyís system of repair. One area of damage concern apoptosis, the bodyís mechanism for arranging for the orderly death or elimination of damaged or defective cells. "When nuclear DNA is damaged, normal cells initiate a response that includes cell cycle arrest, apoptotic cell death, and transcriptional induction of genes involved in DNA repair. Induction of apoptosis is an important response to DNA damage." Bast (16); Wang (10).

The system of apoptosis fails to some extent in lung cancer and .

measurements of apoptotic capacity were associated with survival length.

Tumor suppressor genes perform help induce apoptosis. "P53-specific growth inhibition and apoptosis of tumor cells were observed in both cell lines in vitro."

5.221 Anti-apoptosis genes

5.2211 Cox-2


Cox-2 is a protein produced in times of perceived injury to cells. It appears to frustrate the apoptotic process. Cox-2 inhibitors are being examined as a partial treatment for lung cancer, in part to restore the bodyís apoptotic process

5.23 Tumor Supressor Genes


Tumor suppresor genes play a critical role in cancer:

Although cancer cells use the same cell cycle machinery as normal cells, the cell cycle checkpoints in tumor cells are relaxed. Of the scores of proto-oncogenes and tumor-suppressor genes that have been identified to date, most function in signal transduction pathways that mediate mitogenic stimulation. These signal transduction pathways eventually converge on the cell cycle checkpoint that controls the G0/G1 to S phase transition and activate appropriate CDKs. Influencing the transit of this checkpoint has a major influence on the proliferation of normal and tumor cells by affecting both Tc and growth fraction. Despite the number and variety of these genes involved in signal transduction, relaxation of the G1/G0 to S checkpoint controls in tumor cells is mediated, for the most part, by disruption of two pathways, the Rb and p53 growth control pathways. These two genes, individually, are the most frequently mutated in human cancer cells. Disruption of the Rb or p53 pathways probably occurs in virtually every human cancer. Bast (16)

5.231 P-53

The P-53 gene helps facilitate apoptosis, and acts like a policeman regulating cell development,


p53 protein...mediates several cellular functions: regulation of the cell division cycle, DNA repair, and programmed cell death. DNA repair, and programmed cell death. In response to various forms of genomic DNA damage... the p53 protein can arrest the cell cycle at the G1 to S transition point, thus affording time for DNA repair and preventing duplication of a mutant cell, or alternatively, failing DNA repair, p53 protein can implement programmed cell death (apoptosis). Accordingly, p53 has been dubbed the "guardian of the genome." Etiology of Cancer (7).


5.232 The Retinoblastoma (RB) Gene

The retinoblastoma (RB) gene has a protein that appears to regulate the cell cycle. Most small cell lung cancers have absent or abnormal RB protein. Studies of individuals with abnormalities regarding RB genes showed they develop tumors at 10 times the normal rate. RB abnormalities are also present in NSLC with estimates ranging from 10-60%.

5.24 Growth Factors.

In response to perceived cellular damage and other factors, various growth factors are activated in lung cancer.

5.241 Epidermal Growth Factor

The epidermal growth factor is associated with various types of tumor we develop a chapter to the emerging area of epidermal treatment. A growth factor connects with a corresponding growth factor receptor which begins various cellular processes. Scientist are studying ways of preventing the activation of the growth factor or activation of the corresponding receptor.

Since these treatments target a specific type of cell, their impact upon the overall body will be limited, and the absence of side effects makes these treatments attractive.

5.242 Vascular Endothelial Growth Factor

VEGF is produced and helps the tumor create new blood vessels and connect tissue to facilitate metastasis. Here, too, anti-vegf and vegf receptor drugs are being tested for lung cancer. Vascular endothelial growth factor (VEGF) causes the creation of new blood vessels and the spread of the tumor. One study found that abnormalities of the K-Ras Gene contributed to VEGF. "Of 14 tumors with mutant K-ras genes, 7 cases (50.0%) had high VEGF expression whereas only 39 of the 167 tumors with wild-type K-ras 23.4%) had high VEGF expression." Konishi, (5). Thus, there is a close relationship among growth factors in the complex mechanism of cell signaling and reproduction.



We know that both growth and tumor suppresor genes are involved with the formation of cancers. This helps explain why some smokers contract cancer while others donít. It may be that cigarette smoke causes some changes but only results in cancer when combined with an existing gene abnormality. That is why people with family histories of certain cancers are more likely to contract the disease. It is somewhat like destruction of buildings in a hurricane. Buildings with defects in the foundation will be damaged while others can withstand the assault.

Additionally, we know that exposure to multiple carcinogens increases the risk of cancer. Thus, people who smoke and were exposed to asbestos are more likely to contract lung cancer than people exposed to only one carcinogen. It would simplify analysis to say that smoking causes a change in a dominant gene while asbestos causes a malfunctions in a tumor suppressor gene (or vice versa). However, it appears that each carcinogen can cause changes in both types of genes:


"Various factors, including cigarette smoking, asbestos, and diet, have been reported to correlate with the development of lung cancer. Of these factors, cigarette smoking is believed as the major carcinogen for lung cancer. Recent studies indicate that cigarette smoke carcinogens cause genetic damages at both oncogenes(K-ras) and tumor suppressor genes(p. 53) of lung cancer, and hence initiate and promote the development of lung cancer." Yano, (3).

At this stage in cancer research, we are generally unable to reverse the cell abnormalities though significant progress has been made in identify them. Clinical trials for patients with advanced cancer are experimenting with various means of correcting or mitigating gene malfunctions.



1. Devita, Cancer Principles and Practices of Oncology

2. Carney, Lung Cancer (Arnold Publishing Co., Great Britain, 1995)

3. Yano, Causative Agents for Lung Carcinogenesis, Nippon Rinsho, 2000 May, 58:5, 1017-22.

4. Fleischacker, Molecular Genetic Characteristics of Lung Cancer... Lung Cancer, Vol. 25 (1) (1999) pp. 7-24.

5. International Journal of Oncology 2000 Mar;16(3):501-11.

6. Fleischacker, Molecular Genetic Characteristics of Lung Cancer, useful as Real Tumor Markers, Lung Cancer, Vol. 25 (1) (1999) pp. 7-24.

7. Etiology of Carcinogensis r

8. (no longer available online). Lungcheck was developed to detect lung cancer or even precancerous changes at an early stage.

9. Here is another description of lung cancer development:

The current hypothesis is that at least 10-20 genetic mutations are required to produce a lung cancer cell from the normal one. These mutations cause activation of oncogenes (dominant cellular factors, which stimulate or predispose a cell to divide) and deletion of tumor suppressor genes....The development of cancer is due not only to abnormal cell proliferation with loss of growth control, but also to abnormalities in the cells intrinsic cell death programme, (apotheosis). Proto-oncogenes induce cellular proliferation which activate to oncogenes. Activation may occur by point mutation, over expression, or deletion of genetic material. Oncogenes evaluated for prognostic impact in NSCLS(non small cell lung cancer) include the ras oncogeny, c-erb B-2 oncogenies, also called HER-2 and neu oncogeny and Bcl-2 oncogeny (3). These oncogenes have also been evaluated in clinical trials....

All lung cancer cells produce hormones and peptides, which can function as growth factors and generate growth loops. These include epidermal growth factor, transforming growth factor a, platelet derived growth factor, insulin-like growth factor... Inactivation of genes, that normally regulates cellular growth and thereby have a restraining effect of tumor-genesis (tumor suppressor genes) can lead to uncontrolled cell proliferation, in many cases, inactivation occurs by point mutation of one allele, and subsequently loss of an amount of the genetic material of the other. Prevention of cell division may be based on our increased understanding of the effect of growth factors in lung cancer. There are multiple and diverse simulators, meaning that blocking the action of a single growth factor is unlikely to be effective. However, inhibition of intracellular mechanisms that control multiple growth stimulating inputs offers a more realistic potential for intervention

10. Wang, Fas A6706 Polymorphism, Apoptotic Capacity in Lymphocyte Cultures, and Risk of Lung Cancer, Lung Cancer (2003) 42, 1-8.

11. Qadr Selective Cox-2 inhibition attenuates recurrent tumor growth. J Surg Res. 2003 Oct;114(2):269

11. Jin, Research on expression and control of p16 and p21 by wild-type p53 gene in two lung adenocarcinoma cell lines, Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2003 Oct;20(5):409-12.

12. Shrump, Inhibition of lung cancer proliferation by antisense cyclin D, Cancer Gene Ther. 1996 Mar-Apr;3(2):131-5.

13. State of the Science, Lung Cancer

14. Gregorc, The Clinical Relevance of Bcl-2, RB and P-53 Expression in Advanced Non-Small Cell Lung Cancer, Lung Cancer (2003) 42, 275-81.

15. Mao, Clonal Genetic Alterations in the Lungs of Current and Former Smokers, Journal of NCI, vol. 89, no. 12, (June 18, 1997).

16. Bast, Cancer Medicine (2000).

17. " Antibodies that target VEGFR-1 and VEGFR-2 also inhibit the VEGF signaling pathway. Each of these antibodies inhibits VEGF interactions with a specific receptor, leaving VEGF signaling through the other receptor intact. Both of these antibodies act extracellularly, inhibiting receptors found on the surface of cells....

Several small molecules that inhibit the receptor tyrosine kinase activity of VEGFRs are in development. These molecules function intracellularly, inhibiting activity of the cytoplasmically located kinase domains of the VEGFRs and have variable specificity, potentially inhibiting many different kinases. One small molecule inhibitor, currently in phase II clinical development inhibits VEGFR-1, VEGFR-2, PDGF-R, and c-Kit. Another, also in phase II clinical trials, inhibits the kinase activity of VEGFR-2 but not VEGFR-1. This agent additionally inhibits the kinase activity of HER1/EGFR and Flt-3. Similarly another small molecule inhibitor also prevents VEGFR-2 kinase activity but not VEGFR-1 kinase activity. This agent also prevents the kinase activity of the oncogene c-kit, Flt-3 and PDGF, and is currently in phase II clinical trials."

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