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When we think of lung cancer we typically tend to think it’s the end result of years of smoking cigarettes. But, according to the Centers for Disease Control and Prevention, between 10 and 20 percent of cases of lung cancer (20,000 to 40,000 cases a year) happen to non-smokers, people who have either never smoked or smoked fewer than 100 cigarettes in their life. Now researchers have found that there are different genetic types of cancer for smokers and non-smokers, and that might mean the need for different kinds of treatment.
A team at the National Cancer Institute did whole genome sequencing on tumors from 232 never-smokers who had lung cancer. In an interview with STATnews, researcher Maria Teresa Landi said they called their research the Sherlock-Lung study, after the famous fictional pipe-smoking detective Sherlock Holmes. “We used a detective approach. By looking at the genome of the tumor, we use the changes in the tumors as a footprint to follow to infer the causes of the disease.”
They also got quite creative in naming the three different genetic subtypes they found. Instead of giving them the usual dry scientific names, they called them piano, mezzo-forte and forte; musical terms for soft, medium and loud.
Half of the tumors in the non-smokers were in the piano group. These were slow growing with few mutations. The median latency period for these (the time between being exposed to something and being diagnosed) was nine years. The mezzo-forte group made up about one third of the cases. Their cancers were more aggressive with a latency of around 14 weeks. The forte group were the most aggressive, and the ones that most closely resembled smokers’ cancer, with a latency period of just one month.
So, what is the role of stem cells in this research? Well, in the study, published in the journal Nature Genetics the team found that the piano subtype seemed to be connected to genes that help regulate stem cells. That complicates things because it means that the standard treatments for lung cancer that work for the mezzo-forte and forte varieties, won’t work for the piano subtype.
“If this is true, it changes a lot of things in the way we should think of tumorigenesis,” Dr. Landi said.
With that in mind, and because early-detection can often be crucial in treating cancer, what can non-smokers do to find out if they are at risk of developing lung cancer? Well, right now there are no easy answers. For example, the U.S. Preventive Services Task Force does not recommend screening for people who have never smoked because regular CT scans could actually increase an otherwise healthy individual’s risk of developing cancer.
The Stem Cellar 
Many factors contribute to lung cancer development, such as toxic waste, air pollution and cigeratte smokes. The inhale of toxic compounds has serious consequeces in lung cancer development. As most of the toxic compounds are potentially induced protooncogene of cell and turned on into oncogen. This was supported by transfection study of a single oncogen in cells can induce both tumorigenic and metastatic phenotype in recipient cells. Examples include ras, mos, fes, fms, src, myc, fos and neu. Cancers are heterogeneous, evidence showed that altering a single gene of cells unleashes a complex cascade of events leading to produce many phenotypes and genotypes of cells. Those altering cells grew as clones with different phenotypes and genotype (single gene in different location of each chromosome), tend to releases multiple growth factors to support progressive growth of primary tumor at the primary site. Therefore, the features of dominant subtype of piano with stem cell-like properties, low mutation burden and high intratumor heterogeneity are consistent with the characteristics of primary lung tumor. The multiple clones of tumor in primary tumor had different growth advantage. Clones with growth dominant advantage are metastatic competents, tend to colonize the primary tumor and become metastatic phenotype.
All cellular pathways of cells are regulated by genes expression, the correct signaling of cell is critical to control cell survival, growth, differentiation and behavior. The aberrant of cellular signaling has greater impact on cellular development. Cancers have no stable genotype and phenotype, the progression of tumor may trigger more and more genes become mutated. This phenomenon can be seen in metastatic lung cancer of subtype mezzo-forte and forte. As tumor cells attain metastatic competents, more mutated genes cause their production of and responsiveness to growth factors may be altered, leading to a more aggressive phenotype. That finding indicated that nonmetastatic cells within the primary tumor released increased amounts of suppressive TGFβ and the metastatically competent cells within this same tumor were aberrantly growth stimulated by this traditionally inhibitory factor. Evidence of oncogenic potential of aberrant EGFR showed that, receptors in metastatic tumors cells are constitutively activated independently of ligand binding, results an overstmulation of intracellular control processes may constitutes a strong transforming signal. Metastatic tumors tend to produce a variety of growth factors to amplify growth and direct autocrincity of growth factors production may bestow a growth advantage for tumor expansion. The aberrant growth stimulation of metastatically competent cells by a widely available cytokines might fuel colonization of tumor cells at distant sites in the metastatic process.
Tumor metastasis has high tendency to spread tumor cells from a primary tumor and colonize other sites of the body. The tumor metastasis process is a complex cascade of events, including 1) invasion 2) intravasation and extravasation from the circulation system 3) colonization 4) angiogenesis. At each step of the metastasis process tumor cells must avoid immune recognition and lysis. Therefore, an incomplete metastatic cascade events in subtype of mezzo-forte make them becoming aggressive and patient has latency of survival for ~14 weeks by harbouring those tumors. Whereas, a complete metastatic cascade events in tumor of forte subtype cause them the most aggressive than others, patient with those tumors has shortest survival rate of 1 month.
Tumors are heterogeneous, they have no stable genotype and phenotype. Remarkable heterogeneity in the expression of different antigens has been observed within and between individuals. The standard therapy for each stage of tumors are not tumor specific and selective to effectively eradicate the tumor cells. Tumors can easily develop tumor resistance against chemotherapy to avoid them from destruction. Immunotherapy and gene therapy are alternative choice of treatment, both approaches are specific and selective toward all types of tumors.