Role Of Notch Signaling In Oncogenesis - Essay Example

Role of Notch Signaling in Oncogenesis Introduction Notch signaling pathway is an important intercellular signaling mechanism which is presentin all metazoan organisms. This pathway plays a major role in embryonic development by deciding the fate of binary cells. Notch is named after the notched wing phenotype of mutant Drosophila. Other important functions of the pathway include cell proliferation, regulation of boundary formation between various cell populations and cell death. The Notch pathway includes receptors, ligands, positive and negative modifiers and transcription factors. Notch proteins direct the fate of cells in the developmental stages of various organs and balance between cell proliferation and apoptosis (Wang, Li, Banerjee and Sarkar, 2008). Extensive research in notch pathway has identified either dysregulation or faulty signaling in cancers and many other diseases like multiple sclerosis, tetralogy of fallot and Alagille syndrome. Because Notch signaling pathway is involved in the progression and development of several malignancies, it is considered a novel therapeutic target and if the research on this aspect is fruitful, it can have the highest therapeutic impact in modern clinical medicine (Wang, Li, Banerjee and Sarkar, 2008). The Notch signaling pathway The most important constituents of the Notch signaling pathway are the receptors. There are basically four types of Notch receptors which are single- pass transmembrane receptor proteins. They are Notch1 through Notch 4. Each of these is a heterodimer which is proteolytically cleaved and lies at the surface of the cell. The receptor is made up of 2 domains, the ectodomain and intracellular domain. Both these domains are associated in a calcium dependent, non-covalent interaction. Ectodomain is large and constitutes the outside part of the cell surface. The intracellular domain is smaller and tethered to the membrane. The ectodomain part of Notch receptors interact with certain ligands of adjacent cells. These ligands belong to Jagged and Delta- like families and are named as JAG1, JAG2, DLL1, DLL3 and DLL4. Interaction between the receptor and ligand induces a couple of proteolytic cleavages causing the release of the intracellular domain part of the receptor from the cell membrane. This interaction is mediated by consecutive enzymatic reactions. The intracellular domain then translocates to the nucleus part of the cell and forms a complex with a protein called RBPJ. This reaction leads to displacement of a histone deacetylase-co-compressor complex from the RBPJ protein molecule and then inclusion of MAML1 and histone acetyl transferase which in turn contribute to the transcriptional activation of the target genes of the Notch pathway (Gridley, 2007) like Hes family basic helix-loop-helix members. The receptors and ligands of the Notch pathway are expressed on the surfaces of the cells so that receptor- ligand binding leads to interactions between adjacent cells. Figure-1: Notch signaling pathway (Gridley, 2007) Figure 2: The Four Notch Receptors (Allenspach et al, 2005). Notch signaling plays an important role in the regulation of vascular development and arterovenous differentiation. The primary function of the Notch pathway in this role is regulation of arterial fate specification in endothelial cells. The pathway mediates genetic prepatterning of the initiation of blood flow, much before the commitment of endothelial cell to one of the arterial or venous cell lines. Notch 3 is present only in the smooth muscle cells of arteries and not the veins and hence it regulates arterial specification of vascular smooth muscle cells (Gridley, 2007). Another important function of Notch pathway is the regulation of function and formation of endothelial tip cells (Gridley, 2007). These cells are specialized vascular cells which are present at the tips of various vascular sprouts and help in the guidance of the growth of these sprouts. Notch signaling also regulates the number of tip cells, the extension of filopodia of these cells and the extent of branching of angiogenic sprouts. It plays a role in the physiology, differentiation and functions of vascular smooth muscle cells and causes a repressive effect on the smooth muscle cell differentiation (Gridley, 2007). The repressive effect is mediated via induction of a protein called HEY2. Various studies have demonstrated the expression of Notch pathway genes after vascular injury. Notch pathways also have a role in the neuronal function and development (Gaiano and Fishell, 2002) and in the communication between myocardium and endocardium during the formation of primordial valve and during the development and differentiation of ventricles (Joaquín Grego-Bessa et al, 2007). The signaling of the notch pathway specifies the cell lineage of exocrine and endocrine pancreas (Murtaugh, 2003). In the gastrointestinal tract, the pathways influence the fate of cells into either secretory or absorptive lineages (Sander and Powell, 2004). In the breast, notch signals regulate cell-fate decisions at various stages of development of the mammary gland (Dontu et al (2004). Currently, the most interesting role played by Notch signaling which has created waves of clinical research is the growth, maintenance and metastasis of solid tumors. This article reviews literature about the role of Notch signaling in oncogenesis. Notch signaling and oncogenesis Notch signals regulate tumor behavior in multiple dimensions. They are key regulators of vascular development and proliferation in tumors. Immune responses and cell differentiation in the immune system are very much influenced by Notch signaling and blocking of these signals and thus Notch pathways are critical for tumor behavior. Notch signals also modulate nature killer cells, dendritic cells and T cell proliferation. Many important signaling pathways like Notch, NF-kappaB, Hh, Wnt and Bmi 1 have been identified as regulators of cancer stem cells of the hemopoietic system by virtue of their role in normal hemopoiesis (Cheng and Neil, 2009). Notch pathways also control stem cell renewal and multi-potency. Most of the cancers develop from cancer-like stem cells. These cells are linked with epithelial- mesenchymal transition acquisition and this gives a clue to the role of notch signaling in the progression of human tumors. Notch signaling pathways contribute to the development of cancers in several different ways. The contribution of notch signal in the development of cancer was first detected in T-cell acute lymphoblastic leukemia. This identification happened through detection of a recurrent chromosomal translocation involving Notch 1 gene in a small subset of pre- T-cell leukemias. The translocation is t(7;9)(q34;q34.3) (Allenspach et al, 2002). After this discovery, many other researchers identified notch signaling perturbations in many cancers. Figure 3: Oncogenic Notch signaling pathways in solid tumors (Leong & Karsan, 2006). Certain mutations can lead to over expression of intracellular Notch1 and this has been observed in human T cell acute lymphoblastic leukemia. Various studies have demonstrated the role of Notch pathways in the development of T-cell acute lymphoblastic leukemia. Loss of Ikaros in T-ALL leads to repression of Notch target genes and when this occurs along with suppression of p53-mediated apoptosis, T-ALL results (Demarest et al., 2008). Notch 1 activation can cause maturation arrest of T-lymphoblasts at the CD4+CD8+ double positive stage. This event correlates with subsequent development of T- ALL. Normally, constitutive Notch 1 activity is essential for conversion of common lymphoid progenitors to T lineage. However, failure to down regulate these signals in the double positive stage leads to prevention of further maturation. Notch signals contribute to T-cell transformation by influencing survival and proliferation and not just by blocking only the differentiation aspects (Allenspach et al, 2002). Research has shown that Notch signaling inhibition in several Notch- transformed lines can result in arrest of the cell cycle in G1/G0 stage. Arrest in this stage further leads to apoptosis. This means that targeting notch pathway therapeutically can be used as a form of treatment in T-ALL (Allenspach et al, 2002). Role of Notch signaling in the mammary cancers of rat has been well documented previously. Insertional mutagenesis of the mouse genome by Mouse Mammary Tumor Virus occurs in a recurrent integration site, int-3 and this lies well within Notch 4 gene. Research in the form of murine assays has shown that Notch 3 oncoprotein transforms epithelial cells, causes anchorage- independent growth, invasion of matrix and also loss of contact inhibition (Allenspach et al, 2002). The gene can also cause abnormal proliferation and partial maturation arrest of the epithelium, thus making way for frank adenocarcinoma. In addition to notch 4, notch 1 has also been incriminated in breast cancer. However, there is little information on the role of these pathways in the causation of breast cancer in humans. Whatever information available so far, is on the role of Notch 4 in the development of cancer (Allenspach et al, 2002). Gustafon et al (2009) showed that Harvey- Ras transformation of MCF10A cells causes induction of CCAAT/enhance binding protein beta which inturn activates the Notch signaling pathway. This blocks SIM2 gene expression through a mechanism which is actually independent of C-repeat binding factor 1. It has been previously reported that SIM2 gene is downregulated in breast cancer. Rustiqhi et al (2009) demonstrated the mechanism of notch1signalling deregulation responsible for mammary tumorigenesis. The researchers proposed that interaction of prolyl-isomerase Pin1 with notch1 affects Notch1 activation. Also, Notch1 cleavage by gamma-secretase is potentiated by Pin1 causing increased release of intracellular domain and thus enhancing the transcriptional and oncogenic activity of Notch1. The authors observed a strong relation between high levels of activated Notch1 and Pin 1 overexpression. Notch has been incriminated in the pathogenesis of small- cell lung cancer and there is enough evidence to back this fact. The notch pathway is involved both in normal pulmonary development and oncogenesis. Studies have shown that inducing over expression of intra cellular domains of Notch1 and Notch 2 experimentally can cause G1 cell cycle arrest leading to marked growth suppression. Also, this over expression also contributes to up-regulation of the cyclin-dependent kinase inhibitors (CDKI) p21Cip1 and p27Kip1. These facts favor the involvement of Notch genes in the development of small cell lung carcinoma (Allenspach et al, 2002). In the skin, Notch signaling regulates cell differentiation and growth arrest in the area between basal layer and other cells. In the basal layer, the cells are highly proliferative and undifferentiated. Research has shown that down regulation of Notch pathway is seen in basal cell carcinoma. Whether these genes have a role in other types of skin cancers is still speculative. All the four Notch receptors are expressed in the basal and suprabasal regions of the skin and each of them have distinct functional roles (Allenspach et al, 2002). Altered expression patterns of notch pathways have been reported not only in basal cell carcinoma but also in other skin disorders related to hyperproliferation like psoriasis and wound healing. Notch pathways have been incriminated even in cervical carcinoma. In this cancer, the notch receptors are over expressed. However, some research has shown that in late stages of human papilloma virus infected tumors, Notch 1 is down regulated and that the signals from this gene counteracts the transformation induced by the virus (Allenspach et al, 2002). Basal epithelial cells in the endocervical-ectocervical junction have metaplastic tendencies and these cells stain strongly positive for Notch 1 and 2 and JAG 1 and DLL1 antibodies. Though many researchers argue about the role of Notch pathways in prostate cancer, there is no direct evidence for this. Even in prostate cancer, overexpression of Notch1 has been reported. Bin Hafeez et al (2009) studied Notch 1 expression in human prostatic cancer cells and tissues. In their study, they knocked down Notch 1 receptors in PC3 and 22 Rnu1PCa cells using small interfering RNA. This knock down resulted in drastic reduction of urokinase plasminogen activator and matrix metalloproteinase-9 gene transcripts suggesting the role of Notch 1 in augmenting matrix metalloproteinase-9 gene transcription which is a major contributing factor for prostatic cancer. Notch signaling is implicated in colon tumorigenesis. Meng et al (2009) reported upregulation of Notch 1 receptor in colon cancer progression. The Notch pathway induces prosurvival targets and thus protects cancer cells from apoptosis. Also, when a patient is started on chemotherapy, the cells may upregulate Notch- 1 receptor as a protective mechanism and thus cause chemoresistance. Such a resistance to chemotherapy has been noticed with drugs like 5-fluorouracil, oxiplatin and SN-38. The chemoresistance developed because of induction of Notch 1 intracellular domain by chemotherapeutic agents leading to activation of Hes 1. Meng et al (2009) demonstrated reduction of this chemoresistance and increase of chemosensitivity of colon cancer cells by inhibition of Notch 1 with sulfonamide gamma secretase inhibitors. The researchers also reported in their study that down regulation of notch signaling can cause prevention of prosurvival pathways like phosphoinositide kinase-3/Akt which are seen after chemotherapy with oxaliplatin. Similar reports were presented by Real et al (2009) who demonstrated reversal of glucocorticoid resistance with gamma-secretase inhibitors in T-cell acute lymphoblastic leukemia. It would be interesting to note that Notch activation can be tumor suppressive too in some cancers. This feature is a new concept and merits more research and awareness. .Research has shown that simultaneous activation of Notch 1 and inactivation of Notch 2 has a role in T-cell lymphomagenesis. Also, in B-cell malignancies, studies have shown that Notch signaling can have tumor suppressive effects. In B-cell acute lymphoblastic leukemia, activation of all four types of Notch receptors can result in growth arrest and apoptosis of the cancer cells (Leong & Karsan, 2006). It would be important to note that human basal cell carcinoma lacks activated Notch 1 signaling. In human breast cancer too, Notch 2 is tumor suppressive and Notch 1 oncogenic (Leong & Karsan, 2006). Notch signaling and cancer therapy Universal Notch signal inhibition in the environment of the host can be detrimental for the growth, development and spread of tumors. Valproic acid and suberoyl bis-hydroxamic acid limit growth of neuroendocrine tumors and also decrease secretion of hormones by them by activating Notch 1 pathway (Adler et al, 2008). Such and many other novel therapies can come out of extensive research in the field of Notch signaling and oncogenesis. Conclusion Extensive research has demonstrated the role of Notch signaling in oncogenesis. The role may be tumor suppressive or oncogenic. Hence it can be said that the effect of Notch signaling is probably context- specific. The effects of Notch signaling are dependent on the dose, context and timing. This topic merits more understanding and research in order to help development of more novel cancer treatments. References Adler, J.T., Hottinger, D.G., Kunnimalaiyaan, M., Chen, H. (2008). Histone deacetylase inhibitors upregulate Notch-1 and inhibit growth in pheochromocytoma cells. Surgery 144(6), 956-61. Allenspach, E.J., Maillard, I., Aster, J.C., and Pear, W.S. (2002). Notch signaling in cancer. Cancer Biology and therapy 1(5), 466- 476. Bin Hafeez, B., Adhami, V.M., Asim, M. et al (2009). Targeted knockdown of Notch1 inhibits invasion of human prostate cancer cells concomitant with inhibition of matrix metalloproteinase-9 and urokinase plasminogen activator. Clin Cancer Res.15(2), 452-9. Cheng, X.Y., and ONeill, H.C. (2009). Oncogenesis and cancer stem cells: current opinions and future directions. J Cell Mol Med. [Epub ahead of print] Retrieved on 8th of Feb, 2009 from http://www.ncbi.nlm.nih.gov/pubmed/19175465?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Dontu, G., Jackson, K.W., McNicholas, E., Kawamura, M.J., Abdallah, W.M., and Wicha, M.S. (2004). Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 6, 605-15. Demarest, R.M., Ratti, F., and Capobianco, A.J. (2008). Its T-ALL about Notch. Oncogene 27(38), 5082-91. Gaiano, N., and Fishell, G. (2002). The role of notch in promoting glial and neural stem cell fates. Annual Reviews of Neuroscience 25, 471. Gridley, T. (2007). Notch signaling in vascular development and physiology. Development 134, 2709-2718. Gustafson TL, Wellberg E, Laffin B. (2009). Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPbeta. Oncogene. [Epub ahead of print]. Retrieved on 8th of Feb 2009 from: http://www.ncbi.nlm.nih.gov/pubmed/19169276?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Joaquín Grego-Bessa et al (2007). Notch Signaling Is Essential for Ventricular Chamber Development. Developmental Cell 12 (3), 415–429. Li, X., Gounari, F., Protopopov, A., Khazaie, K., and von Boehmer, H. (2008). Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1. J Exp Med. 205(12), 2851-61. Leong, K.G. and Karsan, A. (2006). Recent insights into the role of Notch signaling in tumorigenesis. Blood 107, 2223-33. Meng, R.D., Shelton, C.C., Li, Y.M. (2009). gamma-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Cancer Res. 69(2), 573-82. Murtaugh, L.C., Stanger, B.Z., Kwan, K.M., and Melton, D.A. (2003). Notch signaling controls multiple steps of pancreatic differentiation. Proc Natl Acad Sci, 100 (25), 14920–5. Real, P.J., Tosello, V., Palomero, T. (2009). Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med.15(1), 50-8. Rustiqhi, A., Tiberi, L., Soldano, A. et al (2009). The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nat Cell Biol.11(2), 133-42. Sander G.R., and Powell, B.C. (2004). Expression of Notch Receptors and Ligands in the Adult Gut. Journal of Histochemistry and Cytochemistry 52 (4): 509–516. Wang, Z., Li, Y., Banerjee, S., & Sarkar, F.H. (2008). Exploitation of the Notch signaling pathway as a novel target for cancer therapy. Anticancer Res. 28(6A), 3621-30. Read More