Novel modeling of cancer: ipsc is answer
1. Department of Medical Biotechnology, Faculty of Medicine, Babol University of Medical Sciences, babol, Iran
Cancer is one of the most complex abnormalities ahead of the human. failure to understanding the molecular dysregulations leads to a theoretical and technical disability in diagnosis, prognosis, and treatment of cancer.(1) also, the unknown various mechanisms of heterogeneous chromosomal abnormalities, uncontrollable cellular plasticity, and reconsideration of various types of cancer are the most important of these challenges.(2) precise molecular studies on cancer require adequate access to malignant cells and cancer modeling in in-vitro conditions. the endeavors of yamanaka et al. that generate induced pluripotent stem cells (ipsc) led to a huge evolution in medicine.(3) transducing of oct4, klf4, sox2, and c-myc transcription factors into somatic cells can reprogram them to the embryonic-like state. the reprogrammed cells can be differentiated into the all human cell lines. ipsc technology faced regenerative medicine, cell therapy and in-vitro modeling of human diseases with the new approaches. patient-derived ipscs can simulate various cells (subsequently various cancers) in in-vitro conditions, and we can understand the dysregulations, mutations, and other disorders involved in cancer, design more effectively target and subsequently novel drug, by molecular approaches (as general or personalized medicine).(4) ipsc-based cancer modeling studies are explored in this article to clarify the importance of ipscs in the future of cancer medicine.
This study was conducted based on our last studies on the application of ipscs in leukemia, as well as other articles indexed in pubmed, scopus, and google scholar databases. in this regard, out of a total of 181 articles have been found (between 2012 to 2018), with the search term "ipsc cancer modeling", 19 articles were reviewed, selected and studied. our findings are presented as a brief review.
Acute myeloblastic leukemia (aml) is a heterogeneous disorder in hematopoietic stem cells caused by genetic mutations, epigenetic dysregulations, and erratic chromosomal rearrangements. (5) a study on aml-derived ipsc showed that the activation of the target genes of myeloid-specific mll can control leukemogenesis in aml patients with 11q23/mll rearrangement, following induction of expression of the meis1-hox fusion protein.(6, 7)
chronic myeloblastic leukemia (cml) is a myeloproliferative disorder in the bone marrow. a study on cml-derived ipsc (cd34+/lin-) showed that chronic myeloblastic-like stem cells are resistant to tyrosine kinase inhibitors. however, olfactomedin-4 can be used as a novel drug in the treatment of cml.(8)
noonan syndrome (ns) is an autosomal disorder that in some cases leads to juvenile myelomonocytic leukemia (jmml). ptpn11 mutations occur in ns and jmml.(9) the study on ns/jmml-derived ipsc clarified the role of mutated ptpn11. it showed that the upregulation of mir-233 and mir-15a are involved in ptpn11-associated jmml myelopoiesis.(10) other studies on leukemia modeling are mentioned in our last research.(11)
myelodysplastic syndrome (mds) as a hematopoietic disorder that caused by genetic mutations, can leads to aml over time.(12) the mechanism of this process was not known until the advent of ipsc technology. the introduction of chr7q deletion in mds-derived ipsc guided the cells slowly to aml-stem cells and determined that haploinsufficient genes (such as hipk2, atp6v0e2, luc7l2, and ezh2) are involved in chr7q deletion in mds patients.(13)
pancreatic ductal adenocarcinoma (pdac) is a very lethal cancer with poor prognosis. the injection of pdac-derived ipscs into naked mice and their proteomic analysis led to the recognition of hnf4a as a novel protein involved in pdac in in-vivo conditions.(14)
glioma is a non-treating cns malignant tumor that has a p53 mutation.(15) a study on p53-knocked down ipsc-derived neural progenitor cells resulted in the introduction of three biochemical agents for the treatment of glioma: nelarabine, letrozole and capecitabine.(16)
other disorders associated with p53 mutation include li-fraumeni syndrome (lfs). lfs progresses to various type of cancers, including osteosarcoma (os) and leukemia.(17) to investigate the role of lfs in os, lfs-derived ipsc was differentiated into osteoblasts. it was found that the p53 gain-of-function mutation with downregulation of h19 guides normal differentiation of osteoblasts to the os.(18, 19)
The introduction of ipsc technology in cancer research can lead to better understanding of the genetic and epigenetic patterns and chromosomal dysregulation of cancer. this approach promises the introducing new therapeutic targets, a faster diagnosis and better prognosis for cancer in the future.
Ipsc, cancer modeling, genetic of cancer, reprogramming