Tumors

I decided to study tumor  this week.  Most people know that tumors are associated with cancer.  They know that tumors are a growth that invades surrounding tissues and will possibly metastasize and spread throughout other organs and tissues.  The fact that tumors can either be benign or malignant is also common knowledge.  So, in an effort to simplify the intricacies of tumor development into comprehensible language, I have created this post.

Origins of Tumors:

(In order to understand tumor development, it is important to have a grasp on the central dogma of DNA.  Information on this topic as well as a screen-cast and animations can be found here: http://molecularbiologyanddisease.blogspot.com/2013/05/central-dogma-of-biology.html)
 
In its simplest form, tumor development is caused by unmediated cellular growth.  Within the human genome there are various genes that control cell growth very precisely.  When an acquired mutation (one that is not inherited but rather occurs by chance) occurs in these genes that mediate cell growth, the genes will not function properly.  If an accumulation of these mutations of present in several of these controlling genes, a person is likely to develop a malignant tumor.  While the cause of these mutations is not definitively known, carcinogens as well as natural aging are thought to contribute to the problem.

There are two foundational elements of tumor development in the human genome namely oncogenes and tumor suppressor genes.  Oncogenes are actually mutated versions of something called proto-oncogenes.  Proto-oncogenes are a sort of gene that controls cell growth by influencing signal transduction and mitogenic signals through protein production.  The output of this protein production allows proto-concogenes to stimulate cell division, inhibit cell differentiation, and arrest cell death. 

Proto-oncogenes can easily mutate and become oncogenes, which is why they are so often associated with cancer.  This activation of an oncogene can occur through a slight modification to the proto-oncogenes original function.  The fundamental mechanisms that cause this activation include insertions,

deletions, and point mutations in promoter regions of proto-oncogenes that cause excessive transcription.  These same sorts of genetic abnormalities can cause hyperactivity in a gene product.  Additionally, gene amplification can occur, which causes extra chromosomal copies of proto-oncogenes to be created.  Finally, a proto-oncogene can become relocated on a new chromosomal site.  This can cause either an elevated level of proto-oncogene expression, or a fusion of a proto-oncogene with a second gene, which can create a protein associated with oncogenic activity.  Additionally, even though humans possess a pair of each chromosome, one from the mother, one from the father, only one chromosome must possess an abnormality in a proto-oncogene for the error to cause cancer.  In other words, oncogenes are a dominant abnormality.  

 There are several types of oncogenes that are responsible for cancer.  However, to give a more in depth look at how proto-oncogenes function, and how when mutated they can cause tumor development I'm going to touch on a few important proto-oncogene proteins that can become over-expressed and contribute to tumor development: the c-fos and c-myc proto-oncogenes.  

According to http://www.uniprot.org/uniprot/P01100.com, the c-fos oncogene "encodes a 62 kDa

protein, which forms a heterodimer with c-jun, resulting in the formation of the AP-1 complex, which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression." This sounds like a whole lot of scientific jargon, but this information can easily be broken done into comprehensible facts.  What this all means is that the c-fos gene codes for a protein that binds with another protein, c-jun.  This forms a larger protein containing the two former proteins that differ in composition, known as the AP-1 transcription factor.  If you have seen my screen-cast on the central dogma of biology, you will know that transcription factors are proteins that regulate gene expression in response to biological stimuli which include cytokines, growth factors, stress, and viral infections.  So, the AP-1 transcription factor takes "extracellular signals" and controls the expression of genes that affect differentiation, proliferation, and apoptosis (programmed cellular suicide).  So, to connect all the dots, when c-fos is over-expressed, AP-1 is also over-expressed.  This causes excessive cellular proliferation as well as reduced apoptosis.  When cells reproduce excessively and do not self-destruct in the presence of a mutation, tumor development occurs.  

Time to discuss the c-myca proto-oncogene.  Same story here.  Scientific journals present the information pertaining to this proto-oncogene in an extremely complex web of scientific terminology.  Here is the gist of it.  http://www.ncbi.nlm.nih.gov/pubmed/18196519.com states that c-myc is a regulator gene that "is believed to regulate expression of 15% of all genes through binding on Enhancer Box sequences and recruiting histone acetyltransferases."  Essentially, c-myc codes for a protein that binds to a specific DNA sequence located upstream a promoter region in eukaryotic DNA.  If you were curious, this sequence is CANNTG, where N can be substituted with any nucleotide.  When the myc protein binds to this DNA sequence called an Enhancer Box, it stimulates gene expression. From there, myc is responsible for a whole lot of up-regulation and down-regulation of genetic components.  When the myc protein is activated is displays many biological effects.  The first of which is the proteins ability to increase cellular proliferation by upregulating cyclins and downregulating p21.  Cyclins are basically proteins that control the rate at which a cell progresses through the cell cycle.  p21 is a protein that inhibits cyclin activity.  So by increasing cyclin production and decreasing p21 production, the myc protein increases cellular proliferation.  Another significant effect of the myc protein is the regulation of cell growth.  Finally, the myc protein is also responsible for increasing cellular apoptosis when necessary by downregulating the production of the anti-apoptotic Bcl-2 protein.  However, when a mutation is present on the c-myc proto-oncogene, it becomes an upregulated oncogene.  This overexpression causes excessive cellular proliferation as well as a lack of cellular apoptosis.  

While I only discussed two proto-oncogenes that can potentially become oncogenes, more than forty proto-oncogenes exist that are linked to different sorts of cancer.  

The second foundation element of tumor development are tumor suppressor genes.  Tumor suppressor genes are essentially the opposite of oncogenes in that they defend a cell from cancer.  However, when tumor suppressor genes become mutated, they lose its function and can allow a cell to develop cancer.  In addition, both alleles for tumor suppressor genes must be affected by a mutation in order for an effect to be manifested.  

The first way in which a tumor suppressor gene can function is by repressing the regulation of the cell cycle.  This can be accomplished by repressing the expression of genes that are necessary for continuing the cell cycle.  When these genes are repressed, the cell cycle cannot continue, therefore halting cell proliferation.  Additionally, tumor suppressor genes can associate DNA damage with the cell cycle.  If DNA damage is present in the cell, the cell is biologically programmed to halt cell division.  From this point, DNA repair proteins can correct the genetic error.  If the proteins fail to do so, then tumor suppressor genes will execute their second function, promoting apoptosis.  This way, a cell that possessing a genetic mutations cannot replicate the mutation and pass it on to other cells.  However, when these tumor suppressor genes become mutated the gene cannot function properly, and the cell loses its defensive mechanism against tumor development.

In conclusion, there are two main ways in which you body can develop a tumor.  EIther a mutation in one copy of a proto-concogene or both tumor suppressor genes will render a human vulnerable to tumor development and cancer.  Hopefully this blog post helped clarify these biological concepts as well as present some interesting information regarding humans and cancer development.

Works Cited:

" What are Proto-Oncogenes? ." THE MEDICAL NEWS | from News-Medical.Net - Latest Medical News and Research from Around the World . N.p., n.d. Web. 21 May 2013. <http://www.news-medical.net/health/What-are-Proto-Oncogenes.aspx>

" Proto-oncogenes to Oncogenes to Cancer | Learn Science at Scitable." Nature Publishing Group : science journals, jobs, and information. N.p., n.d. Web. 12 May 2013. <http://www.nature.com/scitable/topicpage/proto-oncogenes-to-oncogenes-to-cancer-883>

"Proto-Oncogenes and Tumor-Suppressor Genes." www.ncbi.com. W.H. Freeman and Company, n.d. Web. 12 May 2013. <www.ncbi.nlm.nih.gov/books/NBK21662

Sleckman, BP. "Dynamic regulation of c-Myc proto-oncogene exp... [Eur J Immunol. 2008] - PubMed - NCBI."National Center for Biotechnology Information. N.p., 5 Feb. 2008. Web. 12 May 2013. <http://www.ncbi.nlm.nih.gov/pubmed/18

"Proto-oncogene c-Fos - Homo sapiens (Human)." UniProt. N.p., n.d. Web. 12 May 2013. <http://www.uniprot.org/uniprot/P01100>.


Here is a very helpful 3D animation of tumor development as a visual aid: