Overexpression Case Study

(22) In this context of subclinical mutational carriers, individual patient genetic, epigenetic and immunological variables that govern full acquisition of malignant potential are expected to have predictive and therapeutic implications. In addition, investigation of clonal adaptive processes especially those associated with pre-MDS/MDS transition could facilitate understanding of disease pathogenesis.

Therefore, the most notable P53-induced mechanisms in mediating this response are cell cycle arrest and apoptosis [18], which activation depends on the cellular context and the extent of damage [20].

Inflamed tissues from Ulcerative Colitis (UC) patients show increased oxidative and nitrosative damage, leading to accumulation of mutations and dysplastic progression27,28. Infiltrating leukocytes from these patients have increased ROS production in basal conditions and in response to different ligands29. Since TLR4 mediates ROS production in leukocytes22, it is easy to speculate that immune cells drive pro-tumorigenic effects of TLR4. However, bone marrow-transfer experiments in our lab demonstrate that non-immune TLR4 participates in development of neoplasia8. Furthermore, we have shown that epithelial TLR4 activation predisposes to colitis and CAC6. To understand the role of epithelial TLR4 in neoplasia, our research has focused on the

Cytotoxic chemotherapy was first discovered during World War II by Gilman and Philips when they perceived the effect that nitrogen gas (used during WWI) had on the number of human cells proliferating and recognised this as a potential treatment for cancer. From this discovery, biotherapy was born helping to increase our knowledge in how to achieve cell death and tumour control through use of cytokines and monoclonal antibodies (Young et al, 2006). Cancer is often described as unregulated cell growth through a multistep process (Brighton et al, 2005). Brighton (2005) describes the ‘Hallmarks’ of the cancer cell as needing to acquire these six steps in order to develop: ‘self-sufficiency in growth signals, insensitivity to antigrowth signal, avoiding apoptosis, limitless replicative potential, angiogenesis and tumour invasion/ metastasis’. These six Hallmarks of Cancer describe the pathogenesis that a cell undertakes until it develops into a tumour which can then potentially become malignant (Hanahan et al, 2011). While normal cells can control their own proliferation that allows a homeostasis amongst cells, that new cells are born once the old cells have died ensuring that there are enough cells available to fulfil the task at hand. Cancer cells are more neurotic, they interrupt the normal signalling pathway within the healthy cells, and then they begin to grow uncontrollably invading the

Cellular senescence has always previously thought to be an unavoidable and irreversible process wherein old cells stop dividing and undergo a series of chemical and physical changes. These bigger, flatter senescent cells do not die and accumulate in all parts of the body. Senescent cells were only associated with a body’s natural safeguard against cancer; Cells that are cancerous are often fast-tracked to senescence in hopes that it will stop dividing further. However, recent discoveries have shown that senescent cells actually pump out a variety of proteins that cause inflammation, a normally healthy immune response that damages healthy cells in the long run. Almost every discovered

The risk of cancer increases with age, and colon cancer is included in this factor with 62 being the most common age at diagnosis (McCartney & Oberleitner, 2011). Repeated exposure to carcinogens over time can cause mutations in DNA, especially in highly mitotic epithelial cells, resulting in cancerous growths. An immune response in a young and healthy body would destroy the early formation of cancer cells. Unfortunately, individuals of advanced age suffer a decrease in the capabilities of the immune system. This puts them at a higher risk of dysplastic cells multiplying in the colon.

When scientists killed off a certain kind of cell that accumulates in the body with age mice were much healthier and lived about 25 percent longer. The mice didn't seem to suffer any ill effects from losing their so-called senescent cells,these are cells that have stopped dividing, they were though not necessarily because the cells themselves are old. "It's a normal cell that experienced an unusual amount of stress, and it decided to stop dividing," says Jan van Deursen, who studies senescent cells at the Mayo Clinic College of Medicine in Rochester,

The level of activity of Gli genes, and thus Hh-pathway activation, determines skin tumor phenotype: high level signaling is shown to result in BCC and low-level signaling is shown to result in follicular derived tumors such as basaloid follicular hamartoma (BFH) (2). Gli2 is involved in the expression of cell cycle regulation genes in the Shh-pathway such as E2F1, CCND1, CDC2 and epidermal differential genes. Over-expression of Gli2 causes the up-regulation of such cell cycle regulation genes in developing hair follicles. Shh-activation most specifically promotes degradation of the p53 tumor suppressor gene (2), thus repressing transcription of p21, a key suppressor of cyclin E in cell-cycle regulation. Thus, G1 arrest is overrode, and the inability to control cell cycle is promoted: a key feature of cancer. Sufu and Kif7 have overlapping functions in regulating Gli transcription factors. Specifically, Gli2 forms a complex with Sufu to prevent transcriptional activity via preventing accumulation of Gli2 transcriptional factors into the nucleus, thus repressing Hh pathway transduction (3). Sufu also plays a role in stabilizing Gli2 by blocking Spop, an E3 ligase involved in degradation of Gli2 (3). In keratinocytes, Kif7

If left untreated, the cancerous cells continue to divide and multiply, commonly at a rapid rate.

The formation of the dysplastic nevi is associated with an impairment in DNA damage repair, cell growth signaling and reduced susceptibility to apoptotic mechanisms (NEJM 2). In non-familial melanoma, inactivation of phosphatase and tensin homologue (PTEN) is most often present at this stage (source 6, 29-30). In physiological signaling, PTEN functions to inhibit intracellular signaling pathways from growth factors that rely on increasing phosphatidylinositol phosphate (PIP3) concentrations. PIP3 functions to activate protein kinase B (PKB), which induces inhibitory phosphorylation of enzymes that attenuate cell cycle progression and promote apoptosis. A loss of PTEN activity, therefore, facilitates cell immortality and proliferation (source 32 or 51). Interestingly, in mice where PTEN activity is regenerated, melanocytes at this stage are less likely to facilitate turmoigenesis (NEJM 52). In familial melanoma, however, CDKN2A, which encodes for tumor suppressors p16INK4A and p19ARF, is often inactivated (NEJM 33-34). One study demonstrated that, in rats, CDKN2A and PTEN mutations alone are not enough to progress to melanoma. Instead, further mutations must be accumulated before these melanocytes can progress to the third stage (NEJM

The human body is made up of millions of cells that divide continuously either for growth or replacement of worn-out cells-depending on the human stage of development. During the early stages of human development, cell division is rapid for accentuating growth while, in later years of a person’s life, cell division slows down and only takes place for replacement of worn-out or injured cells. This normal cell process is hindered by cancer cell growth. The start of cancer cell growth is manifested in the abnormal cell divisions, or rather out of control cell growth. Some of the notable difference between normal cell growth and cancer cell growth is that while normal cells die, and do not invade other tissues, cancer cell grow

Inflammation is the body’s natural defensive system, it’s responsible for removing and or destroying any harmful stimuli and once the threat has been removed it initiates the healing process. However, if immune activity is unregulated it can transition to chronic inflammation. Chronic inflammation is a persistent and destructive process if prolonged chronic inflammation can promote malignant transformations and even carcinogenesis. In 1863 Rudolf Virchow was the first to suggest an association of chronic inflammation in the development of cancer (Landskron, Fuente, P. Thuwajit, C. Thuwajit, Hermoso, 2014). He hypothesized that cancer progresses from sites of chronic inflammation. Recent advancements over the last couple decades have provided evidence to support chronic inflammations role in tumourigenesis. As a tumour continues to grow and develop, the risk of metastasis increases, resulting in poor prognosis. If

Inflammation is generally an acute process that occurs in response to infection and tissue damage. This protective mechanism involves members of the innate immune system such as macrophages and neutrophils recognizing pathogen-associated molecular patterns (PAMPS) as well as damage-associated molecular patterns (DAMPs) and initiating mediators that increase vasodilation, edema and pain. Long-term inflammation can also occur and leads to a chronic state with conditions favorable for tissue damage and genomic lesions (1,2). Over time this genetic damage can lead to cancer. An example of chronic inflammation leading to cancer development can be seen in patients with ulcerative colitis.

It was earlier thought that up to seven independent genetic hits are necessary for the development and progression of a malignant cancer[Fearon ER and Vogelstein B, 1990], but recent studies suggest that abnormal expression of only three genes might be sufficient for normal cells to convert to cancer cells [Hahn WC et al 1999]. In one such case (H-ras, hTERT, SV40LT) the cancer causing genes were all dominant and transformed proto oncogenes. Also, in this case inactivation of a single oncogene (e.g., mutant ras) can result in tumor regression which implies that in some cases (e.g., mutant ras) continuous expression of oncoproteins is functionally important, non-redundant and indispensable for sustained tumor growth despite a great number of genetic and epigenetic complexities associated with tumor formation. This phenomena is called “Oncogene Addiction” and it provides a rationale for targeted therapy. Thus, Oncogenes have attracted a great deal of interest as molecular targets for cancer therapy in recent years.

Nevertheless, in the majority of cases, it was negative for p16, and even there is a limited number of samples, it cannot be considered as prognostic factors such as in human beings in squamous cell carcinoma carcinogenesis [41]. Further investigations are required to identify if there is any relationship between OSCC and p16 imunoexpression in cows. We suggest evaluation of local lymph nodes, besides the main tumor to clarify these possibilities.