The Notch Signaling Pathway's Role In Cancer Treatment - An Essay.

Describe how details we have learned/discovered about the contribution and role of one specific signalling pathways (chose ONE only from Wnt, Hedgehog, Notch, TGF/BMP) to important developmental steps have led to ideas/practises for treating cancer. 2000 words maximum excluding references , Try to include a figure or diagram or image.

Understanding Notch Signaling Pathway

Cancer is one of the world's greatest killer disease with a slow recovery period. A large proportion of the people have been affected by the negating effects of cancer. The quality of life is significantly affected. Cachexia, muscle and weight loss, a weakened immune system among many other health effects have been found to be associated with cancer. However, the advancements in science and technology have led to the development of better ideas, modes, and means to deal with cancer.

One of the effective methods to employ when dealing with the devastating effects of cancer is by interfering with the Notch signaling pathways. The ways and means developed to deal with the negating effects of the Notch signaling system include the use of smart drugs that operate on specific mechanisms of activation and operation of the Notch signaling pathway.

There are over thirty thousand proteins that are useful in the normal conditions of cells i.e. hemostasis. The Notch proteins play such a significant role in managing the normal hemostatic state of cells.

The pathway has aided in the process of proliferation and differentiation of cells (1) (2). The Notch receptors that have been identified are four in number. These receptors are Notch 1, 2, 3 and 4 (4) (3) These four Notch receptors have been found to be similar in appearance. In complete contrast, their extracellular and cytoplasmic domains are different (5).  There are two ligands that have been found to be associated with mammals. These ligands have been identified to be delta-like or serrated like in makeup due to similar structural homology. Two serrated like ligands have been identified to be jagged 1 and jagged 2 (6).

The extracellular domains found within the makeup of the Notch proteins have been found to poses a distinct characteristic -they are made up of multiple repeats and also contain the epidermal growth factor that is associated with ligand binding (7). Targeting the Notch proteins with drugs can be most effective in controlling and even eliminating potential malignancies at the end of the day. It is also important to note that there is ligand independent signaling mechanism in the Notch signaling cycle. However the negative regulatory region (NPR) in the Notch system aids in inhibiting both ligand dependent and independent processes (8).

The knowledge collected about the Notch proteins can be very effective when dealing with malignancies and tumors of various kinds. Not only can the Notch proteins and their ligands be inhibited in various types of cancers but also the enzymes within the Notch cycle be stopped hence derailing the onset or progression of a malignant tumor. The prevention of activity of notch, in the development pathogenesis of various kinds of cancer has been seen to be highly significant since it also crosstalks with other important oncogenes in the cancer development process.

Notch Signaling Pathway in Cancer Progression

In addition, an understanding of the Notch activation system is necessary to treatment modalities associated with cancer. Notch activation is effected when a ligand binds to a surrounding Notch receptor within the environs of cells (9). Once it is activated it leads to the expulsion of the Notch intracellular domain (NICD). This is by means of a systematic process of proteolytic connections by means of metalloprotease, y-secretase and tumor necrosis factor (9).

The second phase of activation can occur on the surface of the cell. It is caused by the connection of a complicated association of proteins which include nicastrin and presenilin among many others.The prevention of y-secretase activity has been found to be very effective in the prevention of the cleavage of receptors of the Notch origin, therefore, the prevention of transduction genes. The Notch genes are maintained in a dormant or inactive state as a result of this inhibition (2) (6) (9).

Genes of the notch origin also play a crucial role in the development of this type of cancer. There are genes that are tissue specific. Other are metastatic and operate on the surface of many organs and tissues. This information significantly shows that Notch has a significant potential in affecting the progression of cancer within body systems.

It is crucial to recognize that the effect of Notch on the body systems has been found to be both beneficial and harmful. Notch can either cause proliferation, survival, differentiation and even apoptosis. On the other hand, Notch may end up causing tumor generation and may end up becoming oncologic or anti-proliferative – paradoxically (1). It has been found that the presence of Notch in human malignancies is usually upregulated rather than downregulated.  

The knowledge obtained from the activity of notch is effective in various kinds of tumors and is offering promising results. Pancreatic cancer is the 4^th of death in the US (10).  In 2009 alone over 35,000 people died as a result of pancreatic cancer in the US. The longevity of life for cancer survivors within the states is below 20% for all stage one patients. And the survival rate for a five year period is below five percent (10).

High prevalence of notch 1 and 2 and its associated ligands and target genes is significant to the progression of cancer (11-16). GSI (which inhibit the activity of y-secretase) aid in avoiding growth and development o cancer. (12). This sign shows the importance of medical knowledge in the activity of the Notch.

Notch Signaling Pathway in Treatment Modality

Downregulating the activity of notch siRNA or treatment by use of GSI is proportional to a decrease in the proliferation rates caused by pancreatic cancer decreased apoptosis, led to a decrease in migration of cells and a decrease in invasive abilities of pancreatic cancer cells.

However,  Notch is up-regulated in a very significant way in the case of Gemcitabine-resistance cancer cells of pancreatic origin, which. It has recently been identified that Notch is involved in the operation of MicroRNA 34 which is responsible for the operation and functioning of pancreatic stem cells and renewal through the direct modulation target notch.  This shows that the inhibition of Notch could possibly show a better method for killing the cancer cells and in the process create a better prognosis for the patients who have been affected by pancreatic cancer.

Other than the application of the knowledge attained from Notch in the management of cancer of the pancrease, it is also effective in the treatment modalities in prostate cancer. Cancer of the prostate is one of  the most diagnosed and common types of cancer among men. It is the 2^nd leading cause of cancer death in the US (10).  The overall development and prognosis of prostate cancer involve several numbers of signaling pathways in addition to Notch. This is especially because Notch has also been found to be overly expressed along the lines of prostate cancer cells.

Patients with prostate cancer are found to express the Notch 1 protein in significant proportions. This is especially found in patients with osteoblastic cancer of the prostate  Jagged 1 has is expressed in significant proportions in metastatic cancer of the prostate other than localized prostate cancer. For effective management of prostate cancer, it is advisable that  the inhibition of Notch 1 and Jagged 1 is crucial is performed.  

Downregulating the proportion of Notch and Jagged is effective in preventing metastasis and increasing cell death. Androgen receptor is associated with the Notch. More studies, however, need to be performed to identify the functioning and effectiveness of Notch in the management of cancer of the prostate. However, it is known that using drugs that downregulate the activity of notch and Jagged  have proven effective in the management of prostate cancer.    

In addition to pancreatic and prostate cancer, breast cancer is another killer disease among a great population of women with cancer. It is the second most common malignancy found among women.  There are several treatment modalities that have been used to manage breast cancer. Among this, the treatment modalities that have been used to manage breast cancer are chemotherapy, surgery, and radiation. These modalities work most of the time, however, in some cases they may fail to be effective and tumor recurrence may be experienced. Cumulatively a high level of expression and representation of Notch and its ligand are the causes for poor progress among breast cancer patients. Notch cross talks with other connections in the breast cancer cycle hence derailing further improvements in the overall state of patients. High percentages of Jagged and Notch in patients is also been a cause of poor progression with cancer patients due to the synergistic effect elicited by these two.  

Notch has also been identified to be responsible for the regulation of slug, estrogen receptor, Slug, and many other crucial signaling proteins in breast cancer management. By preventing the activity of Notch breast cancer is controlled more effectively. Targeting the Notch signaling is appropriate method of controlling cancer of the breast.

In combination with the other types of cancers already discussed, lung cancer is also a member of this killer cancerous diseases. It is able to kill more than three thousand people day by day. The progression of lung cancer and worsening prognosis of patients is related to notch. Notch 1 and Notch 2 are contained in high levels this type of cancer (10).Oxygen levels have been found to affect the expression of Notch because the expression of Oxygen is useful in the controlling of hypoxia and cancer of hypoxic in nature (10)

Conclusion

In conclusion, the importance of inhibition of Notch as a treatment modality cannot be over-emphasized. Not only is the inhibition of the ligands, enzymes, and molecules involved in the notch signaling effectively in the treatment process of cancer but also in the termination of  stem cells associated with cancer. The context of notch termination is also essential. Notch sometimes plays a very positive function in the activity of cells. Drug modalities working on specific target types of Notch and in specific locations are effective in improving patient’s prognosis

Reference list.

1. Morgan TH. The theory of the gene. Am Nat. 1917;51:513–544.
2. Miele L, Osborne B. Arbiter of differentiation and death: Notch signaling meets apoptosis. J Cell, Physiol. 1999;181:393–409. [PubMed]
3. Almén MS, Nordström KJ, Fredriksson R, Schioth HB. Mapping the human membrane proteome: a majority of the human membrane proteins can be classified according to function and evolutionary origin. BMC Biol. 2009;7:50
4. Ilagan MX, Kopan R. SnapShot: Notch signaling pathway. Cell. 2007;128:1246
5. Le Gall M, De Mattei C, Giniger E. Molecular separation of two signaling pathways for the receptor, Notch. Dev Biol. 2008;313:556–567. [PMC free article] [PubMed]
6. Miele L. Notch signaling. Clin Cancer Res. 2006;12:1074–1079. [PubMed]
7. Weinmaster G. The ins and outs of Notch signaling. Mol Cell, Neurosci. 1997;9:91–102. [PubMed]
8. Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306:269–271. [PubMed]
9. Fortin ME. Notch signaling: the core pathway and its posttranslation regulation.Dev Cell. 2009;16:663-647 [PubMed]
10. Jemal A, Siegal R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics. CA Cancer J Clin. 11. Buchler P, Gazdhar A, Schubert M, Giese N, Reber HA, Hines OJ, Giese T, Ceyhan GO, Muller M, Buchler MW, Friess H. The Notch signaling pathway is related to neurovascular progression of pancreatic cancer. Ann Surg. 2005;242:791–800. [PMC free article] [PubMed]
11. Miyamoto Y, Maitra A, Ghosh B, Zechner U, Argani P, Iacobuzio-Donahue CA, Sriuranpong V, Iso T, Meszoely IM, Wolfe MS, Hruban RH, Ball DW, Schmid RM, Leach SD. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell. 2003;3:565–576. [PubMed]
12. De La OJ, Emerson LL, Goodman JL, Froebe SC, Illum BE, Curtis AB, Murtaugh LC. Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci USA. 2008;105:18907–18912.[PMC free article] [PubMed]
13. De La OJ, Murtaugh LC. Notch and Kras in pancreatic cancer: at the crossroads of mutation, differentiation and signaling. Cell Cycle. 2009;8:1860–1864. [PMC free article] [PubMed]
14. Kimura K, Satoh K, Kanno A, Hamada S, Hirota M, Endoh M, Masamune A, Shimosegawa T. Activation of Notch signaling in tumorigenesis of experimental pancreatic cancer induced by dimethylbenzanthracene in mice. Cancer Sci. 2007;98:155–162. [PubMed]
15. Mullendore ME, Koorstra JB, Li YM, Offerhaus GJ, Fan X, Henderson CM, Matsui W, Eberhart CG, Maitra A, Feldmann G. Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer. Clin Cancer Res. 2009;15:2291–2301.[PMC free article] [PubMed]
16. Wang Z, Banerjee S, Li Y, Rahman KM, Zhang Y, Sarkar FH. Down-regulation of Notch-1 inhibits invasion by inactivation of nuclear factor-{kappa}B, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res. 2006;66:2778–2784.[PubMed]