“Ptendose dictates cancer progression in the prostate” authored by LloydC. Trotman, Masaru Niki, Joson A. Dyke, Zohar A. Dotan, Antonio DiCristofano, Andrew Xiao, Alan S. Khoo, Pradip Roy-Burman,. Norman M.Greeneberg, Terry Van Dyke, Carlos Cordon-Cardo, Pier Paolo, Pandolfiand published on October 27, 2003 in PLoS Biology.
Thearticle explores the impacts of Ptendose variation on progression of cancer. Ptenis one of the cancer suppressor genes that are located on thechromosome. The gene is usually located in chromosome 10q23 that iseasily lost when one is suffering from cancer. The gene oftenundergoes mutation or somatic deletion, especially when one issuffering from prostate cancer. Consequently, the effect of Ptendose in progression of prostate cancer is investigated by generatingPtenmouse mutant series that have a declining Ptenactivity. The mouse mutants are generated through inactivation ofPtenat varying levels. The researchers then investigate the impact ofvarying levels of Ptendose in mouse mutants with varying levels of Ptengene inactivation. The results enhance the readers’ understandingof the how Ptendose acts as the key determinant of the progression of cancer,especially the prostate cancer.
Theexperiment was conducted using the mouse as non-human models. Thetarget genome constructs (Ptenmouse mutant series) were obtained by cloning kpnI-BamHI fragmentthat contained 5’ Ptengenomic DNA and Xbal fragment that contained 3’ genomic DNA. Thesouthern blot analysis was procedure was used to verify thesuccessful transmission of the mutant allele. The target allele (Pten10xP-neo)and the floxed allele (Pten10xP) were obtained by mating Pten10xP-neo/+mice with EHA-Cre transgenic mice. The specific prostate Pteninactivation was achieved by crossing the Pten10xP/10xPwith PB-Cre transgenic mice. The researchers obtained MEFs bycrossing Ptenhy/+and Pten+/-mouse. Cells were harvested and mRNA extracted via TRIZOL method andcDNA produced using the RT-PCR. The LX Echo Speed Sigma Scanner wasused during the MRI analysis to assess the tumor establishment ineach mouse.
SincePtenheterozygous mutants are known to be viable and prone to tumor, theresearchers had to generate mutant that allow the levels of Ptento be reduced below the normal levels available in Pten+/-.This was accomplished through homozygous recombination and generationof alleles that would express the wild-type Ptenand take advantage of transcriptional interference at reduced levelsof Pten.The process resulted in the generation of viable and fertile mutantsthat harbored Ptenhy.A further reduction of the dose of Ptenresulted led to embryonic lethality of the subjects, whichfacilitated the generation of male and female mice containing Ptenhy/-.However, the experiment failed to meet the expected target of 25 %mutants because only 10 % of the mutants with Ptenhy/-were born. This was inconsistent with the Mendelian ratios. Thefindings indicate that about 40 % and 75 of Ptenhy/-males and females got lost during the process of gestation. This wasa confirmation that a reduction in Ptendose had taken place in the mutants, which in turn resulted inlethality.
Thetest for prostate tumorigenesis indicated that the 25 % of the micehad the signs of local invasion. Reducing the dose of Ptenfurther resulted in immense prostate hyperplasia, which acceleratedthe progression of tumor from high grade PIN to locally invasive CaP.The test for effect of complete Pteninactivation indicated in prostate cancer showed that a completepenetrance resulted in rapid enlargement of prostatic lobes. Thismeans that the experiment successfully proved the fact thatinactivation in the case of prostate cancer diffuses CaP and resultsin invasion at complete penetrance. In addition, a test for theeffect of varying levels of Ptendose on prostatic epithelium indicated that a progressive reductionof the dose affects the rate of prostatic epithelia proliferation andleads to molecular changes that in turn determine the history oftumor and lesions progression.
Thefindings reported in the article makes it possible to reclassifymalignant and preneoplastic pathological entities that previouslyappeared similar. The experiment used multistep and linear processthat facilitated the separation of two pathological and anatomicalentities that is the invasive CaP and the normal prostaticepithelium. In addition, the findings indicated that inactivation ofa single Ptenleads to hyperplasia of the epithelium while a complete inactivationresults in human-like tumor prostate hyperplasia. The two types oflesions are different in that the first one affects the epithelialelements while the second one affects both the stroma and epitheliaelements. The findings indicating that a reduction in the dose ofPtenhas a significant therapeutic implication. This is because about 80 %prostate cancer patients demonstrate a loss of Ptenalleles and still have the normal allele. This means that the locallyinvasive and the high grade PIN carcinomas can be treated or evenprevented through the modulation of the expression of the retainedpart of alleles.
Thearticle is presented in a very comprehensive way, which makes it bothinteresting and enlightening. The most important lesson learned fromthe article is the fact that Prostate cancer can be treated oncondition that pharmacologists are able modulates the expression ofthe other part of Ptenallele that does not get lost when one contracts the cancer. Thearticle can be modified by rearranging its different sections toreflect the normal scientific procedure. For example, the methodologysection should be placed after the literature review and creation ofnew headings, such as the literature review and conclusion. Thefuture studies should focus on the field application of theprocedures in the treatment of CaP in human since the presentfindings were obtained suing the non-human models.
Trotman,C., Niki, M., Dotan, A., Koutcher, A., Cristofano, D., Xiao, A.,Khoo, S., Roy-Burman, P., Greenberg, M., Dyke, T., Cordon-Cardo, C. &Pandolfi, P. (2003). Ptendose dictates cancer programs in the prostate. PLoSBiology,1 (3), 385-396. DOI: 10.1371/journal.pbio.0000059