Monday, December 5, 2011

Interfering with Pancreatic Cancer Growth – Role of Interferon Regulatory Factor-2 in Pancreatic Tumorigenesis

Apple CEO Steve Jobs; 2011 Nobel Prize Laureate Ralph Steinman; actor Patrick Swayze; actor Michael Landon; opera singer Luciano Pavarotti; comedian Jack Benny; actress Donna Reed; musical composer Henry Mancini. These well-known individuals, despite varying career paths, share a rather tragic connection: each has lost his or her life as a result of pancreatic cancer. Pancreatic cancer, or pancreatic carcinoma, has the highest mortality rate amongst all major cancers. Within 5 years of diagnosis, approximately 94% of patients will die from this form of cancer. Just this year, it is estimated that 44,030 cases of pancreatic cancer will be newly diagnosed, while approximately 37,660 patients will have died as a result of the disease [2]. Cigarette smoking, obesity, type II diabetes, blood types A/B/AB, and loosely defined genetic influences may present elevated risk for developing pancreatic carcinomas; however, the majority of patients diagnosed with pancreatic cancer do not exhibit any identifiable risk factors. Pancreatic cancer is a rather aggressive malignancy, and the high mortality rate is attributed to the difficulty in detecting the cancer at an early stage, as well as to the complexity involved in its development. Because this form of cancer has frequently reached advanced stages by the time of diagnosis, removing the tumor through surgery is not often a treatment option. When the tumor has spread beyond the pancreas (metastasized) and is not operable, chemotherapy alone, or in combination with radiation therapy, is utilized. Traditionally, the chemotherapy drug selected for treatment is gemcitabine [3]. Such limited and largely unsuccessful therapeutic options available for pancreatic cancer patients underscores the importance of defining new mechanisms for treatment.

While most people have probably heard of pancreatic cancer, few know what this organ is or does. To clarify, the pancreas is a large gland organ located behind the stomach, part of the digestive and endocrine systems. It is responsible for producing hormones such as glucagon, insulin, and somatostatin (endocrine function) and for secreting digestive enzymes into the small intestine (exocrine function). The endocrine pancreas is composed of approximately a million cellular clusters termed islets of Langerhans, with four main cell types in the islets (a cells, b cells, g cells and PP cells). The exocrine pancreas is made up of specific cells responsible for producing/secreting digestive enzymes and of a system of ducts lined by epithelial cells that secrete bicarbonate – a salt-rich substance – into the small intestine.
Within each of us, the trillions of cells that comprise our bodies perpetually undergo processes of damage and repair. Every time that a new cell is generated in order to replace a spent cell, a mechanism is implemented to try to produce an exact and flawless copy of the original cell it will supersede. There are extraordinarily intricate systems applied at the nuclear level to essentially edit and fix any mistakes made during cell division; however, errors occur daily in spite of these processes. Typically, if faults are made, they are minimal with no effect on the cell or they are ultimately corrected so that there are no changes to the function of cellular proteins. In rare instances, the DNA mutation experienced in a new cell will eventually cause the cell to attain a growth advantage. This is the case in a subset of potential alterations to genes involved in growth regulation, differentiation, or controlled cell death (apoptosis). A cell that undergoes one of these types of mutations acquires the capacity to divide in an unregulated way, free from the checks and balances normally managing cellular replication cycles. This cell is considered the cell of origin in a tumor and carcinogenesis ensues. Ultimately, malignant conversion of a mass occurs when one of the pre-cancerous cells experiences a mutation that tips the balance towards an invasive growth pattern. Highly mutated and malignant cells proliferate and divide in a completely deregulated manner, forming the primary tumor.
In the case of pancreatic cancer, a carcinoma can form in either the endocrine pancreas (called ‘islet cell’ or ‘pancreatic neuroendocrine’ cancers) or in the exocrine pancreas. Exocrine pancreatic cancers, referred to as adenocarcinomas grow far more rapidly than islet cell cancers and are typically more difficult to treat as a result. Approximately 95% of patients with pancreatic cancer have adenocarcinoma. The pathogenesis of pancreatic cancer is attributed to the alteration of several target genes. In a recently published study by Cui and colleagues, the potential involvement of IRF-2 (interferon regulatory factor), a transcription factor over-expressed during tumorigenesis, was investigated in pancreatic cancer patients [1]. IRF-2 acts to inhibit the IRF-1-mediated transcriptional activation of the genes induced by interferon (IFN)-a, -b, and –g. One of the immune mechanisms in which tumorigenesis can be inhibited or prevented is through the production of major pro-inflammatory molecules (cytokines), including IFN-g. IFN-g has powerful anti-angiogenic effects that prevent tumors from fostering the blood vessels needed to support growth. It is also capable of inducing the establishment of a collagen capsule around a tumor, thereby impeding metastasis [4]. Therefore, when IRF-2 is over-expressed, IRF-1 is inhibited such that IFN-g is prevented from carrying out tumor-suppressive functions.
The authors first looked into the possible role of IRF-2 in pancreatic cancer by analyzing 30 tumor samples collected from adenocarcinoma patients. They examined protein levels of IRF-2 through immunohistochemistry, and found that IRF-2 was elevated in tumor samples when compared with the associated normal tissues samples. The expression of IRF-2 was principally localized in the nuclei of pancreatic cancer cells, and these results were confirmed using PCR (examining mRNA levels of particular proteins; in this case, of IRF-2 and b-actin, a component of the cytoskeleton in cells) and western blot analysis (detecting the protein level of IRF-2) of tumor and normal tissue. IRF-2 was further associated with the clinical features and survival of the patients. Specifically, the authors determined that the expression of IRF-2 was positively correlated with tumor size, differentiation, and TNM (tumor, node, metastasis) stages. The median survival time of the patients in this study was 14.2 months; however, statistical analysis revealed that patients who exhibited high expression of IRF-2 displayed a substantially reduced median survival (11.5 months) compared to patients with relatively lower expression of IRF-2 (16.5 months). An in vitro study was subsequently conducted using two pancreatic cancer cell lines (MIAPaCa-2 and PANC-1 cells) to analyze the effects of IRF-2 on the growth of pancreatic cancer cells. The authors knocked down the expression of IRF-2 in these cells and found that this inhibited the growth of the pancreatic cancer cells but not their migration. There was also a reduction in colony formation after down-regulating IRF-2 expression. This supports the role of IRF-2 in both the growth of pancreatic cancer as well as in tumorigenesis. Next, the impact of IRF-2 knockdown on the expression of particular molecules implicated in cell proliferation and apoptosis was examined. Expression of proteins promoting apoptosis (PARP, BAX, and cleaved caspase-8) was up-regulated in response to the down-regulation of IRF-2, while expression of proliferation-related proteins (cyclin D1 and PCNA) was down-regulated. The pro-apoptotic proteins examined have each been previously shown to inhibit development of pancreatic cancer while the expression of cyclin D1 has been found to contribute to tumorigenesis in pancreatic cancer [5]. Thus, the findings described above illustrate that IRF-2 may facilitate pancreatic cancer cell growth by preventing apoptosis and accelerating cell expansion. When the authors silenced the expression of IRF-2 in pancreatic cancer cells, they became sensitized to apoptosis. This suggests that IRF-2 has an oncogenic role on pancreatic cancer cells, again, by influencing proliferation and apoptosis.
The findings of Cui and colleagues provide evidence that IRF-2 is involved in the pathogenesis of pancreatic cancer. Not only was IRF-2 found to be highly expressed in pancreatic tumor samples, but it was additionally demonstrated to play a significant role in the growth of pancreatic cancer cells. Increased expression of IRF-2 is inversely associated with the overall survival of pancreatic cancer patients. With the results of this study in mind, the down-regulation of IRF-2 may present a potential therapeutic target in treating pancreatic cancer. Further research will need to be completed in order to expand upon the findings in this paper, explore the possibility of IRF-2 as a treatment target, as well as to elucidate any adverse effects that this type of therapy might have. At least for now, this study offers a step in the right direction towards successfully fighting pancreatic cancer.
Primary Reference:
1. Cui, L., Y. Deng, Y. Rong, W. Lou, Z. Mao, Y. Feng, D. Xie, and D. Jin. 2011. IRF-2 is over expressed in pancreatic cancer and promotes the growth of pancreatic cancer cells. Tumor Biol. doi: 10.1007/s13277-011-0273-3.
3. Pancreatic carcinoma. (2011). In A.D.A.M. Medical Encyclopedia. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001283/.
4. Mak, T. W., & Saunders, M. (2011). Primer to the immune response, academic cell update edition. Academic Press.
5. Chung, D. C. 2004. Cyclin D1 in human neuroendocrine: tumorigenesis. Ann NY Acad Sci. 1014: 209–217. doi: 10.1196/annals.1294.022.
6. Vincent, A., J. Herman, R. Schulick, R. Hruban, M. Goggins. 2011. Pancreatic cancer. The Lancet. 378: 607-620. doi: 10.1016/S0140-6736(10)62307-0.

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