Reversibility of oncogene-induced cancer
ABSTRACT Cancer can largely be conceived as a consequence of genomic catastrophes resulting in genetic events that usurp physiologic function of a normal cell. These genetic events mediate their pathologic effects by either activating oncogenes or inactivating tumor-suppressor genes. The targeted repair or inactivation of these damaged gene products may counteract the effects of these genetic events, reversing tumorigenesis and thereby serve as an effective therapy for cancer. However, because they are the result of many genetic events, the inactivation of no single mutant gene product may be sufficient to reverse cancer. Despite this caveat, compelling recent evidence suggests that there are circumstances when even the brief interruption of activation of a single oncogene can be sufficient to reverse tumorigenesis. Understanding how and when oncogene inactivation reverses cancer will be important in both defining the molecular pathogenesis of cancer as well as developing new molecularly based treatments.
- SourceAvailable from: Syed Rizwan Hussain
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- "Tumors generally have a number of genomic aberrations, and no single genetic alteration is thought to be enough to cause tumor progression . Some mutations are necessary for initiating and/or developing tumors but are not necessary for late-stage tumor maintenance . The c-kit gene plays an important role in the development of multiple cell types, including haematopoietic cells, germ cells, mast cells and melanocytes. "
ABSTRACT: C-kit gene is a transmembrane tyrosine kinase that acts as type III receptor for mast cell growth factor and cellular migration, proliferation, survival of melanoblasts, haematopoietic progenitors and primordial germ cells. Apart from the scant information about the pathologies associated with loss-of-function mutations, few reports have proposed role of the c-kit gene in case of carcinogenesis. Apparently, in breast cancer the involvement of c-kit gene mutations has been considered as a rare phenomenon. Thus, we designed our study with aim to investigate the c-kit gene mutation in breast cancer, and their correlation with clinico-pathological findings. We performed mutational analysis of the c-kit gene in 58 cases of malignant breast cancer. With the aim to ascertain the variety of mutations at exon 8, 9, 11, 13, 15 and17 of c-kit gene in breast cancer, we have done PCR-SSCP followed by DNA sequencing. In breast cancer the c-kit gene mutation rates were 3.44% (02/58) in exon 8, 5.17% (3/58) in exon 9, 5.17% (3/58) in exon 11, 3.44% (2/580 in exon 13, 3.44% (2/58) in exon 15 and 5.17% (3/58) in exon 17, respectively. The overall c-kit mutation frequency in exons 8, 9, 11, 13, 15 and 17 was determined to be 25.86% (15/58). Our study indicates to specify the role of c-kit proto-oncogene mutation in breast cancer. The result signifies that c-kit gene plays a poor role in prognosis of ductal and lobular carcinoma.Journal of the Egyptian National Cancer Institute 06/2012; 24(2):97-103. DOI:10.1016/j.jnci.2011.10.003
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- "They represent an important challenge because disruption of Oct-4 expression after knockdown using RNA interference impaired self-renewal and was detrimental to both tumour and metastasis developments in a p53À/À context. These last observations have to be compared with previous reports showing the regression of tumours observed when ectopic expression of Oct-4 is stopped (Hochedlinger et al., 2005), when forced downregulation of Oct-4 expression prevents tumour growth in a mouse teratoma model (Gidekel et al., 2003) or when differentiation of dysplasic or neoplasic cells occurs upon loss of oncogene expression (Felsher, 2004; Shachaf et al., 2004; Hutchin et al., 2005). Indeed, OCT-4 behaves like an essential factor driving both self-renewal and tumourigenic/metastatic potentials in the TICs described here, and any approach aiming to reduce its expression may lead to strategies effective to reduce cancer pathogenesis, with a minimal impact on the function of somatic cells where its expression is barely observed and not required for selfrenewal (Lengner et al., 2007). "
ABSTRACT: Tumour-initiating cells (TICs) are rare cancer cells isolated from tumours of different origins including high-grade tumours that sustain neoplasic progression and development of metastatic disease. They harbour deregulated stem cells pathways and exhibit an unchecked ability to self-renew, a property essential for tumour progression. Among the essential factors maintaining embryonic stem (ES) cells properties, OCT-4 (also known as POU5F1) has been detected in tumours of different origins. Although ectopic expression results in dysplasic growth restricted to epithelial tissues, overexpression expands the proportion of immature cells in teratomas. However, OCT-4-expressing cells have not been purified from spontaneously occurring tumours, thus information concerning their properties is rather scant. Here, using p53-/- mice expressing green fluorescent protein and the puromycin resistance gene under the control of the Oct-4 promoter, we show that OCT-4 is expressed in 5% onwards of the undifferentiated tumour cell populations derived from different organs. OCT-4 expression was low as compared with ES cells, but was associated with a 'stemness' signature and expression of the chemokine receptor CXCR4. These cells displayed cancer stem cell features, including increased self-renewal and differentiation ability in vitro and in vivo. They not only formed allografts containing immature bone regions but also disseminated into different organs, including lung, liver and bone. Experiments based on RNA interference revealed that Oct-4 expression drives both their engraftment and metastasis formation. This work points out the crucial contribution of Oct-4-expressing TICs in the hierarchical organization of the malignant potential, leading to metastasis formation. Consequently, it provides an appropriate model to develop novel therapies aiming to strike down TICs by targeting self-renewal genes, therefore efficient to reduce tumour growth and metastatic disease.Oncogene 09/2011; 31(19):2438-49. DOI:10.1038/onc.2011.421 · 8.56 Impact Factor
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- "Inactivation of MAPK Accompanies Tumorigenesis Tetsu et al. Neoplasia Vol. 12, No. 9, 2010 brief interruptions of the activities of a single oncogene such as H-Ras, K-Ras, c-Myc, and EGFR can reverse cancer . There have been no reports of reversibility of c-Kit–induced cancer in mice. "
ABSTRACT: The Ras/mitogen-activated protein kinase (MAPK) pathway is considered to be a positive regulator of tumor initiation, progression, and maintenance. This study reports an opposite finding: we have found strong evidence that the MAPK pathway is inhibited in a subset of adenoid cystic carcinomas (ACCs) of the salivary glands. ACC tumors consistently overexpress the receptor tyrosine kinase (RTK) c-Kit, which has been considered a therapeutic target. We performed mutational analysis of the c-Kit gene (KIT in 17 cases of ACC and found that 2 cases of ACC had distinct missense mutations in KIT at both the genomic DNA and messenger RNA levels. These mutations caused G664R and R796G amino acid substitutions in the kinase domains. Surprisingly, the mutations were functionally inactive in cultured cells. We observed a significant reduction of MAPK (ERK1/2) activity in tumor cells, as assessed by immunohistochemistry. We performed further mutational analysis of the downstream effectors in the c-Kit pathway in the genes HRAS, KRAS, NRAS, BRAF, PIK3CA, and PTEN. This analysis revealed that two ACC tumors without KIT mutations had missense mutations in either KRAS or BRAF, causing S17N K-Ras and V590I B-Raf mutants, respectively. Our functional analysis showed that proteins with these mutations were also inactive in cultured cells. This is the first time that MAPK activity from the RTK signaling has been shown to be inhibited by gene mutations during tumor development. Because ACC seems to proliferate despite inactivation of the c-Kit signaling pathway, we suggest that selective inhibition of c-Kit is probably not a suitable treatment strategy for ACC.Neoplasia (New York, N.Y.) 09/2010; 12(9):708-17. DOI:10.1593/neo.10356 · 5.40 Impact Factor