Lung Cancer - Diagnosis, Causes, Treatment, and Living With It
...ted into the blood and a scanner records where the material goes to. This shows whether or not cancer has spread to the bones. After a physician determines that a patient has lung cancer, the next step is to decide whether or not the patient should go through surgery. The doctor will carefully review the images and data from the patient and try to figure out whether metastasis (the spread of the cancer to other parts of the body) has occurred. The mediastinal lymph nodes are a good indication of this, and are usually removed in patients who undergo lung cancer surgery. If the lymph nodes are negative (cancer free), there is a good chance metastasis has not occurred and surgery is a treatment option. On the other hand, if the lymph nodes contain cancerous cells, the patient is not a candidate for surgery and will probably have to undergo chemotherapy and other treatments. Small cell lung cancer is responsive to chemotherapy, but usually reoccurs within a year of treatment, leaving less than 15% of the patients alive 2 years post-surgery. The Causes of Cancer Cancer is the most well known and deadly of all human diseases. Every year, it infects hundreds of thousands, and proves fatal in nearly 1/3 of cases. But Cancer is no ordinary infliction. It isn’t a bacterial infection, or a virus. Cancer is a complex genetic disease that is acquired throughout one’s life. In order to begin to understand cancer, one must first understand genetics. As we know, DNA is the molecule which all genetic processes are based on. It provides for its own replication, for the division of cells, and for the creation of proteins. However, DNA is not perfect. There are over 4,000 known diseases that stem from genetic faults, and many others which have certain hereditary predispositions based on one’s genetic makeup. DNA can be damaged in many ways, which include, but are not limited to, translation errors, radiation, and carcinogens (chemicals which are known to cause cancer, how convenient). While DNA has ways of repairing itself, these repairs are not always successful, and so the damage can be passed on to future copies of the cell. As we have discussed in our studies of protein creation, even the slightest change in the DNA of a cell can cause a drastic change in the proteins it creates. These altered proteins can prove useless, or even dangerous to a cell. Some of these proteins can actually trigger rapid cell reproduction, and when they do, Cancer can onset (“Lung Cancer Home Page”, National Cancer Institute). While Cancer is not generally known as an inherited genetic disorder, it is well documented that certain people have a predisposition to the disease. Having a family history of Cancer can slightly increase one’s chances of becoming affected by the disease. Usually, these predispositions manifest themselves in methods such as an altered metabolism rate for breaking down carcinogens, or even an altered ability for the DNA to repair itself. Because cancer stems from damaged DNA, a diminished ability to repair damages increases ones vulnerability to cancer. While many types of cancer run in families, lung cancer is rarely seen as a hereditarily biased disease. (“What Causes Lung Cancer”, American Lung Association online) It is well known that chronic smoking and second-hand smoke are leading catalysts for the development of lung cancer, which is by far the most violent carcinoma. The increased risk from smoking is directly proportionate to the intensity and duration of exposure to the chemicals found in tobacco products. While it is true that quitting smoking does diminish the chances of being diagnosed with lung cancer, it is by no means foolproof. Studies show that 10 years of abstaining from smoking reduces the chances of developing lung cancer to 1/3 of their normal values. However, smoking is not the only cause of lung cancer. Radon, a noble gas which can enter households through cracks in the foundations of homes, is considered to be another common contributor to developing the disease. It is said that Radon contributes to around ten percent of all lung cancer cases, and causes over 15 thousand deaths per year. Other carcinogens known to lead to lung cancer are asbestos, uranium, arsenic, and certain petroleum products. Lung cancer can develop even after this cessation, as the toxins that kickstart the disease never fade from the linings of the lungs. The disease generally stems from the bronchial epithelium (basically the tissue of the inner wall) lining the passages of the lung, which can be heavily damaged by the buildup of tar and other toxins found in tobacco products. Lung cancer has proven to be one of the most difficult cancers to fight off. According to the OncoDiagnostic Laboratory (www.oncodx.com) , lung cancer is the leading cause of death in both men and women. There are over 160 thousand cases reported annually, and less than 15% of those afflicted with lung cancer ever fight it off. Of the many types of carcinoma, lung cancer is by far the most fatal, causing more deaths than colon, breast, and prostate cancer combined. Mortality rates have not been ameliorated in the last 20 years, and this problem vexes scientists who are trying to find more successful methods of fighting off lung cancer. Genetic mutations that lead to lung cancer are classified in two areas: proto-oncogenes, and tumor suppressant genes (TSG’s). These genes generally regulate cell division, and it should come as no surprise that damage to these genes can result in a reduced ability to slow cell division rates. Proto-oncogenes create proteins that act as growth signals. They are normally turned off, and must be activated by a substrate, but after proper mutation, they become simply oncogenes. The proteins they create cease to require activation, and allow inordinate cell growth. Oncogenes can also initiate wanton stimulation in the production lines of CDK. It is clear that cells are protected from becoming cancerous due to only one genetic change; several genes must be infected before cell division begins to lose control. You can see why the cell takes so many safeguards to protect itself. Some of the most common mutations occur in the p53 and p16 TSG’s, and in the short arm of the third chromosome, which happens to be a veritable breeding ground for cancer. The p53 gene, located in the chromosomal region 17p13, has been one of the most scrutinized genes in the development of carcinomas. It is a tumor suppressor gene, and its normal function is to regulate the cell cycle checkpoints in the G1 and G2 phases. It is especially used to respond to DNA damage during these phases of the cell cycle. Generally speaking, it is a fragile gene, which is prone to inactivation by numerous means, and its inactivation is a hallmark of identifying tumor cells. (“p53”, OncoDiagnostic Laboratory) According to research by Tina Hernandez-Boussard and Pierre Hainaut (“A Specific Spectrum of p53 Mutations in Lung Cancer from Smokers: Review of Mutations Compiled in the IARC p53 Database”, Tina M. Hernandez-Boussard and Pierre Hainaut) of the International Agency for Research on Cancer, G-T mutations are frequent in the alteration of the p53 tumor suppressant gene, and the most frequently affected codons include 157,158,179,248,249, and 273. In fact, lung cancer patients suffer from unique codon mutations at 248, 249, and 273, which suggests that behavior is a greater influence on lung cancer development than is genetics. Another often studied gene by researchers of lung cancer is the FHIT (fragile histidine triad) gene. In studies done by the Cancer Research Campaign, the damping of FHIT expression was a very common abnormality in lung cancer, and that by tampering with FHIT expression, the likelihood of developing lung cancer is increased. (“Loss of Fhit expression in non-small-cell lung cancer: correlation with molecular genetic abnormalities and clinicopathological features”, British Journal of Cancer online) In fact, nearly 70% of all lung cancer patients show signs of losses of FHIT activity. Allelic loss at the FHIT gene is an early step in the development of certain cancers, and like many tumor suppressant genes, it is very fragile and easily damaged. This damage isn’t limited to allelic loss; it can also be caused by simple mutations and promoter methylation (this is when chemical alteration of important DNA sites prevent proper translation and transcription, and we noted this in class with those arrows up and down towards our DNA figure). Carlo Croce, of the Kimmel Cancer Center says “These genes appear to be deleted… with great frequency in some of the most common human tumors”. He is also quoted as saying “In fact, FHIT is mutated…predominantly by deletion (allelic loss), even more frequently than p53 in some of the most common human cancers”(“Cancer Genetics”, Eugene Russo). Another common protein involved in cancer development is the p16 tumor suppressant. P16 is a regulator protein, and is coded at the INK4a gene (location 9p21). It manifests itself as a cyclin-dependent kinase inhibitor (remember CDK? Yeah, this protein aims to prevent phosphorylation). It generally binds to CDK 4 and 6, and inhibits CDK’s phosphorylating. As with many other suppressor and regulator genes, INK4a is quite fragile, and this gene falls prey to somatic mutations and allelic deletions in many cases of cancer. Mutations in INK4a are quiet dangerous, as an inactive p16 protein allows CDK 4 and 6 to phosphorylate without repression, which can lead to an increased rate of mitosis. This cannot single handedly cause cancer, but it is a leading mutation in the development of carcinomas (“p16”, OncoDiagnostic Laboratory). Research by scientists at the Shanghai Medical University shows that p16 deficient cells undergo a rapid exit from the G2 and mitosis phases, and that the research was found linked to radiosensitivity of lung carcinomas. Other research has found this radiosensitivity to be a possible weakness in cancer, and that a reenabling of p16 in infected cells (“Restoration of the p16 gene is related to increased radiosensitivity of p16-deficient lung adenocarcinoma cell lines”, Journal of Cancer Research and Clinical Oncology). Another gene commonly associated with the development of lung cancer is the C-myc proto-oncogene, whose function induces the transcription of DNA. C-myc creates a basic region-helixloop-helix leucine zipper (HLH-zip) which aids the expression of certain target genes. This HLH-zip generally works with a partner protein, which is created by the C-max gene. The partner zip protein helps regulate transcription of target genes, and is used to keep the C-myc activated. Once the C-myc gene has been infected, however, it binds incorrectly to the partner protein, and the C-mad zip protein can no longer keep the C-myc active. As such, the C-myc ceases its transcription of the target genes. Apparently, these target genes include other proto-oncogenes and TSG’s, and so the cessation of C-myc’s transcription of target genes indirectly causes increased cell growth by limiting the production of cell regulator proteins (“Oncogenes and Proto-Oncogenes, intouchlive.com). To wrap up, lung cancer is caused mainly by acquired genetic changes. These changes are most often found in TSG’s and proto-oncogenes, a few of which were mentioned above. These mutations are generally caused by smoking or from radon poisoning, and as the lungs have a poor cleansing system, the alterations can occur even after one ceases exposure to the carcinogens. Thankfully, one mutation cannot affect this horrible infliction, though it can develop through a mutation of multiple vital genes. It is well known that mutation of TSG’s and proto-oncogenes are present in every single case of lung cancer, and that no other genes mutations are found consistently in lung carcinomas. Treatment Possibilities Surgery The foremost treatment for non-small cell lung cancer is surgery to remove a tumor. “Surgery that removes the tumor and surrounding tissue offers the best chance of recovery. However, surgical treatment has some very real restrictions. Tumor size, metastasis to the lymph nodes, and the type of cancer must all be considered.”(“Lobe and Lung Removal: Lobectomy and Pneumonectomy”, www.treatments-for-lung-cancer.com). When surgery is treated as an option, special consideration must be made for the size of the tumor, the type of lung cancer, the location and the stage in which the cancer is. Three types of surgery are possible: wedge resection and segmentectomy, lobectomy, and pnumonectomy. Wedge resection and segmentectomy surgical procedures are preformed when the cancer is in its early stages and only the affected tissue is removed. Lobectomy procedures remove an entire section of the lung with the hope that the procedure will eliminate all traces of the cancer. Pnumonectomy procedures remove an entire lung to rid the organ of cancerous tissue that may be hard to detect (“Lobe and Lung Removal: Lobectomy and Pneumonectomy”, www.treatments-for-lung-cancer.com). Chemotherapy Amongst the many and sundry new and presently advancing treatments for cancer, none have proven more prevalent or efficacious than chemotherapy, the employment of chemicals to destroy developing cancer cells. The treatment – one of the original and frequently employed techniques – works through the inhibition of the division and spread of cancerous cells by preventing its initial growth (“What is Chmotherapy?” CancerBACUP). Chemotherapy, unlike surgery and various other treatments for the disease, proves particularly effective in its ability to treat widespread cancers. Since the therapy relies upon the movement of certain treatment chemicals throughout the body, its affects suffuse the entirety of the body, serving doubly as a preventative measure for expansion and a termination of those extant cancer cells. This capacity for total-body-treatment is one of chemotherapy’s salient benefits, as the two other most common treatments, surgery and radiation, only treat locally, often failing to inhibit the propagation of cancerous cells already infiltrating the blood stream. However, though these differing treatments may not suffice independent of one another, when used in conjunction the treatments’ combined affects most effectively combat the spread and development of cancerous cells. To best comprehend the reasons for chemotherapy’s efficacy in the treatment of cancer, one must first have a firm command of those intricate and convoluted processes of the cell cycle. The fundamental design of the treatment rests upon its inhibitory affect on the process of cell division. In order for cells to propagate throughout the body and, in consequence, ensure the restoration of their expired predecessors, each cell undergoes a four-step sequence of division. The first phase of which is called G1 in which the cell prepares to replicate its chromosomes. In second stage, called S, DNA synthesis occurs and the DNA is duplicated. Thereafter follows G2 in which the RNA and protein duplicate. And the final, termed M, is the juncture of actual cell division. In this ultimate stage, the duplicated DNA and RNA separate and move to opposite ends of the cell, dividing the cell into two identical, functional copies. In order to arrive at the desired affect, the chemotherapy – in whichever drug form – will seek to affect these malignant cells in three distinct ways: • Sufficiently and destructively altering the DNA of the targeted cells to prevent mitotic division and, in effect, isolating it until its expiration. • Preventing the creation of new DNA strands in the S phase, thereby precluding any possible development and subsequent proliferation. This is achieved through the introduction of an inhibitory drug targeted at the requisite nucleotide bases for DNA creation. • Cessation of the mitotic process of the cells (at the final stage) through the destruction of spindle fibers (necessary for the separation of newly created DNA), thereby terminating its full development. (“How does Chemotherapy Work?” ACS Online) Though certainly numerous and widely varying in chemical structure, these chemotherapy drugs are divided into five expansive categories based upon their structure and means by which they achieve the desired end of cancerous cell termination or inhibition of further proliferation. More specifically, they are classified upon the matter of which section of cell they seek for alteration or destruction in the following: Alkylating agents: chemicals whose purpose is for direct assault on the DNA of the cancerous cells. Though effective at any time of the cell cycle, they reach maximum efficacy at the stage of DNA synthesis. Alkylating agents are generally administered orally or intravenously; some examples of which include Cyclophosphamide, Mechlorethamine, and Cisplatin. Nitrosoureas: similar to alkylating agents, these chemicals seek by disrupting the natural functions necessary for the reparation of damaged DNA. As with alkylating agents, nitrosoureas may be administered either orally or intravenously; some examples of which include Carmustine and Lomustine. Antimet Abolites: chemicals whose principal affect is the cessation of DNA synthesis. These chemicals achieve end through the assumption of a chemical structure similar to that required for DNA synthesis of the S phase, thereby preventing its actual development and immediately terminating division. As with the two previous, antimet abolites may be administered orally or intravenously; some examples include 6-mercaptopurine and 5-fluorouracil. Anti-tumor antibiotics: chemicals designed to bind to DNA, inhibiting RNA and, ultimately, DNA synthesis. These drugs prevent the DNA from rebinding, effecting the cell’s immediate expiration. Antitumor antibiotics may be administered intravenously and include Doxorubicin and Mitomycin-C. Plant alkaloids: a treatment, which seeks the complete and total di...