Disease Path Case Study

Cancer, medically called ‘tumorigenesis’ (Thaker, Lutgendorf, & Sood, 2007, p.430) occurs when cells in the body orient themselves for malignant growth. Such cells show ‘self-sufficiency in growth signals’, are ‘insensitive to anti-growth signals’ and have ‘limitless replicative potential’ (Thaker, Lutgendorf, & Sood, 2007, p.430). Once a particular set of cells become malignant, the malignancy can spread to other set of cells in different organs due to ‘crosstalk’ between the affected cells and their surrounding ‘tissues’ and ‘micro-environments’(Thaker, Lutgendorf, & Sood, 2007, p.430).

One study by Shuijun Zhanga et al had shown the ABT-737 induced apoptosis of hepatocellular carcinoma cells (HCC) by the transcriptional repression of Myeloid cell leukemia 1 (Mcl-1). Shuijun Zhanga et a. had shown that NCTD could affect apoptosis by the modification of the B-cell lymphoma 2

Esophageal carcinoma, the eighth most common cancer in the world, includes squamous cell carcinoma and adenocarcinoma (Sun, Lin, Chen, Liang, &Hsieh, 2015; American Cancer Society, 2015). Squamous cell carcinoma is simply damaged esophageal cells; however, adenocarcinoma occurs when glandular cells replace squamous cells in the esophagus (American Cancer Society, 2015). While squamous cell carcinoma was once the most common form of esophageal carcinoma in the United States, adenocarcinoma has taken its place with speculation placed towards the increase of gastroesophageal reflux disease (GERD) (Baldwin, 2015). These two manifestations of cancer account for approximately 90% of diagnosed esophageal cancers, while the remaining 10% of esophageal

consists of ComP, the histidine kinase, and ComA, the response regulator.2 There are two known

Squamous Cell Carcinoma – Accounts for 20% of non-melanoma cancers and causes death in about 10% of affected patients.

If the APC protein were to experience a nonsense mutation, the most common mutation in regards to this specific genetic disease, the destruction complex would not perform correctly and the wnt-signaling pathway would be stimulated. Problems begin to arise when “the Wnt/Beta-catenin pathway is activated [by] a Wnt ligand [binding] to seven-pass transmembrane Frizzled receptor and its co-receptor, low-density lipoprotein related protein 6 (LRP6) or its close relative LRP5” (MacDonald, et. al 2009). Once the wnt-signaling pathway is stimulated, a Wnt-Fz-LRP6 complex forms and takes in the Dishevelled (Dvl) protein, resulting in the phosphorylation and activation of the recruitment of the axin complex, destruction complex, to the receptors. (MacDonald, et al 2009). Due to the phosphorylation within the Wnt-Fz-LRP6 complex, the axin complex is not able to phosphorylate Beta-Catenin, which leads to the excessive accumulation of the protein in the cytoplasm. Researchers witnessed the development of numerous intestinal adenomas in transgenic mice with stabilized mutant Beta-catenin, therefore the results suggest that dysregulation of Beta-catenin is a key oncogenic event that follows the loss of APC function. (Tarapore, et. al 2011). The loss of the destruction complex’s normal activities results in elevated levels of Beta-catenin and downstream effectors such as CCND1,

Integrated motif activity response analysis (ISMARA) - a bioinformatic tool to predict altered transcription factor activity - predicted the E2f family as upregulated in ENT1-/- AF tissue. E2f transcription factors are associated with cell cycle progression from G1 to S phase.14 Indeed, the expression of numerous E2f transcription factors was significantly upregulated in ENT1-/- AF tissue. We will further investigate the role of E2f factors in ENT1-/- AF tissues using a combination of RT-qPCR, immunohistochemistry and western blotting to examine tissue specific changes in the IVD and their association with markers of cell proliferation (i.e. Ki-67, PCNA). Further, we will use established protocols for AF cell isolation and culture to assess whether changes observed in vivo are recapitulated in vitro. Additionally, shRNA knockdown in WT AF cells will be used to identify specific E2f members responsible for increased cell proliferation, and genes downstream of altered E2f

The site and nature of the cancer will influence how it invades other areas of the body. The extent of

This ability of malign cancer to make their way across basement membrane and into blood vessels is what makes cancer so fatal and impossible to be cure by surgery alone. The result of metastasis and invasion in normal tissue by cancer cells are often seen as one of the distinctive features of malignancy (Ruoslahti 1996). Even though the ability of invasion and metastasis are one of the hallmarks for cancer, these abilities are not unique to cancer cells as it can also occur during the early development stage of the embryo, in healthy organisms and in many noncancerous diseases (Mareel & Leroy 2003). It does not matter whenever the organism has developed benign or malign cancer, all cancer cells have the ability to disturb the normal cell cycle and threaten the survival of the organism.

At the G-protein- coupled receptor proteolytic site, the N terminus of PC1 is cleaved, but the extracellular domain is still noncovalently attached to the membrane-bound portion of the protein. The two different cleavages release C-terminal tail fragments that move to the nucleus with parts of the Wnt pathway, STAT6/p100, and with other regulators of transcription. PC2 stimulates one of the C-terminal tail cleavages. This requires the PC2 to be able to function as an ion channel. Both direct and indirect interactions allow the polycystin proteins (PC) to inhibit and/or stimulate pathways involved in cell division and growth. If there are defects in the gene encoding of either PC1 or PC2 it can lead to unusual ion secretion, gene transcription, and cell proliferation, which can then result in the formation of fluid-filled cysts. As a cyst begins to grow bigger it leads to the displacement of the normal kidney functions. Also the formation of the cyst in the kidneys reduce its functional

Aberrant expression of p16INK4a, either high or low, is found frequently in human cancers (Table 1). In colon cancer, two different patterns of p16INK4a overexpression have been reported. The first pattern is related to senescence in serrated adenomas, which have malignant transformation associated with p16INK4a downregulation (Refs. 138, 139). The second pattern is characterized by a very low p16INK4a immunostaining in normal mucosa, with a progressively higher expression in aberrant crypt foci, non-serrated adenomas, primary carcinomas and metastatic tumors (Ref. 87). A similar pattern was observed in skin cancer where p16INK4a expression increases from relatively low levels in pre-malignant lesions to high levels in in situ and infiltrating carcinomas (Ref. 140). In breast cancer, p16INK4a was negative or low in normal ductal epithelium, but a progressive increase was found in benign lesions and carcinoma (Refs. 88, 89). Increased nuclear p16INK4a protein expression compared with normal epithelium has been reported in pre-neoplastic and tumor tissues of the gallbladder (Ref. 141). Therefore, inactivation of

Nasopharyngeal carcinoma (NPC) is a rare head and neck cancer, although in Asian individuals of southern Chinese descent observed high incidence of NPC (Lo et al., 2004). The pathogenesis of NPC is multifactorial connecting with viral, genetic and environmental factors. The Epstein-Barr virus (EBV) with nonkeratinizing NPC in Asian populations has been well documented in 1970s (Shanmugaratnam and Sobin, 1991), however, it is not clearly associated with non-Asian patients (Raab and Epstein, 2002; Lo et al., 2004). Inactive EBV infection is found in NPC and high-grade dysplasia, however is not obviously present in the normal nasopharyngeal epithelium (Raab and Epstein, 2002). Previous studies show unclear

From the genetic point of view the progression of tumor that culminates with metastasization, occur as a result of activation of oncogenes and/or by the inactivation or inhibition of onco- suppressor genes(Fearon, 1990)

It also has been shown that cyclin D1 is a downstream target of the β-catenin–TCF complex and therefore when continually activated allows cells to proceed through cell cycle and continue tumor growth. In support of this, expression of the dominant-negative form of TCF, lacking the β-catenin binding domain, in colon-cancer cells strongly inhibits expression of cyclin D1 causing cells to arrest in the G1 phase of the cell cycle due to the lack of activation of cyclin D1 [23]).

Gemcitabine sensitivity/resistance of cancer cells can't be defined by only single determinant and may be needed the contribution of several main factors such as Gemcitabine activating enzymes, stemness (Wnt signaling pathway), alterations of membrane-bound nucleoside transporters (hENT1, hCNT1 and hCNT3), Epithelial to Mesenchymal Transition, apoptosis and the main signaling pathway involved in tumorigenesis (NF-κB, PI3K-Akt), cell cycle and DNA repair (loss of p53) [4-5].