Evaluation of CEMIP in Pancreatic Cancer

Pancreas is an important retroperitoneal organ with exocrine and endocrine functions. Pancreatic cancer (PC) is one of the most lethal diseases among all cancer types. It moved from the fourth to the third leading cause of cancer-related death in the United States and is anticipated to become the second around 2020. It accounts for about 3% of all cancers in the United State and about 7% of all cancer deaths.

The estimated number of PC cases in Egypt in 2013 was 2,226, and it is projected to increase and be 2,836 and 6,883 in 2020 and 2050 respectively. The overall age-adjusted PC mortality rate in Egypt was 1.47/100,000 population and analysis of the regional distribution showed significant variations in rates among provinces with Northern provinces having higher rates than Southern regions.

The asymptomatic nature of early PC, the lack of sensitive and specific tools to diagnose early disease, and the lack of response to most forms of treatment all contribute to the high mortality rate of pancreatic cancer. This poor outcome could be largely due to the late diagnosis. The expression profiles of PC had been widely studied, revealing several molecular factors affecting various aspects of PC.

Tumors of pancreas are divided into: Non-endocrine tumors which maybe benign or malignant and endocrine tumors.

The diagnosis of PC is usually based on radiology [computed tomography (CT) and magnetic resonance imaging (MRI)] or invasive endoscopic techniques [ultrasound endoscopy-fine needle aspiration (EUS-FNA), endoscopic retrograde cholangiopancreatography (ERCP), and explorative laparoscopy. Imaging diagnosis method is a normal method for clinical tumor diagnosis. But due to the various defects of the image device, it is usually to combine several kinds of technologies for diagnosis. Moreover because of the low sensitivity and specificity, the methods are often used in the diagnosis of high risk groups, rather than early detection. Therefore, it is urgently needed to develop new methods for early diagnosis of cancer.

An ideal diagnostic method for PC should definitively distinguish malignant lesions from benign lesions, provide precise tumor staging, and detect early-stage disease and preneo-plastic conditions. There are many challenges in the early detection of PC, including its asymptomatic nature, the lack of a characteristic radiological manifestation and the absence of specific molecules in body fluid. Therefore, convenient and highly sensitive diagnostic tests for screening PC are probably more important than tests with good specificity but moderate sensitivity.

Various types of tumor markers are used for diagnosing PC. The tumor markers carbohydrate antigen19-9(CA 19-9) and carcinoembryonic antigen (CEA) are the ones most closely tied toPC. But these proteins don't always go up when a person has pancreatic cancer, and even if they do, the cancer is often already advanced by the time this happens. Sometimes levels of these tumor markers can go up even when a person doesn't have pancreatic cancer. For these reasons, CA19-9 and CEA aren't used to screen for pancreatic cancer, although a doctor might still order these tests if a person has symptoms that might be from pancreatic cancer. These tests are more often used in people already diagnosed with pancreatic cancer to help tell if treatment is working or if the cancer is progressing.

Although CA 19-9 is known as a pancreatic cancer biomarker, it is not commonly used for general screening, owing to its low sensitivity and specificity. In particular, false-negative results in the segment of the population with Lewis blood type A-B- and false-positive results in patients with obstructive jaundice limit the specificity of CA 19-9 for PC. Therefore, development of novel diagnostic markers is required for the early detection of PC.

CEMIP (KIAA1199), defined as cell migration inducing protein currently is located in chromosome 15q25.1, which appears in the nucleus and cytoplasm. It is a secreted protein (153KDa) rather than a transmembrane protein. Its mutation site was reported to cause hearing loss due to the folding change of protein structure, meanwhile the over-expression of CEMIP referred to dreadful invasion and uncontrolled proliferation of tumor with distant metastasis and limited survival opportunity of patients. Especially, over-expressed CEMIP also protected malignant tumor from strict microenvironment in hypoxia, low glucose and cracked barrier, leading to enhanced adaptability of tumor by stimulating the epidermal growth factor receptor (EGFR), fibroblast growth factor receptors (FGFR) pathway. CEMIP plays an important role in cytokine pathway and its over-expression in tumors provide a novel target for individual therapy. Targeting CEMIP would thereby dysregulate the cytokine pathway which would in turn, decide the growth and death of the vicious tumor cells.

Increased expression of CEMIP has been reported in various cancers including: breast, colorectal and gastric. Several studies have investigated the role of CEMIP in pancreatic cancer. It has been reported to be associated with early detection, cancer cell migration, invasion, and poor prognosis. Suh., 2016 suggested that CEMIP may be useful for detecting pancreatic cancer at an early stage, while Koga., 2017 demonstrated its association with prognosis in PC.

Primary screening using circulating biomarkers followed by confir¬mative diagnosis based on imaging and patho¬logic results might be the future strategy for diagnosing PC.