Pancreatic cancer is the fourth most common cause of cancer death in the US and the seventh most common cancer death globally.

It has a 5-year survival of 5%, with disease mortality remaining as high as 99%. Over 330,000 deaths worldwide are attributed to pancreatic cancer every year, with 338,000 cases diagnosed in 2012. About 55% of these cases occur in the developed world.

The pancreas is a gland that lies adjacent to the stomach and produces hormones like insulin, glucagon and somatostatin that are important for the regulation of digestion, as well as enzymes (including trypsin, chymotrypsin, lipases and amylases) that play a critical role in digestion and are secreted into the duodenum through two pancreatic ducts. Although the pancreas is composed of a large number of different cell types, due to the number of hormones and enzymes it produces, 85% of pancreatic cancers are pancreatic adenocarcinomas¹, which are derived from the cells that make digestive enzymes.

The symptoms of pancreatic cancer include jaundice, abdominal or back pain, weight loss, changes in stool and/or urine color and loss of appetite. Unfortunately, these symptoms are sufficiently general, and frequently do not occur until the tumor is well advanced so that pancreatic cancer is often not diagnosed until the disease is advanced.² Pancreatic cancer is rare in patients under the age of 40 and more than half the cases occur in patients over 70.³ The risk factors for pancreatic cancer include smoking, diabetes and obesity. 5-10% of pancreatic cancer is thought to be hereditary. The relatively late diagnosis of pancreatic cancer and the proximity of the pancreas to the duodenum and liver (the bile duct joins the pancreatic duct before entering the duodenum) as well as it’s position next to the stomach means that local spread of pancreatic cancer is a significant problem and the prognosis for patients with pancreatic cancer is generally poor. The diagnosis of pancreatic cancer is usually based on one or more imaging techniques (ultrasound, CT) and ultimately, biopsy.

Pancreatic cancer is treated with surgery, radiation therapy and chemotherapy (in addition to palliative care). Drugs used to treat pancreatic cancer include nucleoside analogs (gemcitabine 5-FU) that inhibit nucleic acid synthesis, taxanes (paclitaxel, docetaxol), which inhibit microtubule formation, and platinum containing compounds (cisplatin, oxaliplatin), which are alkylating agents, and inhibit DNA synthesis.

Investigations of the genetic based of pancreatic cancer have identified 3 genes that are associated with the hereditary cases: PALB2, BrCa2 and p16. PALB2 and BrCa2 are both involved in the same DNA repair enzyme complex, while p16 plays an important role in regulating the cell cycle and is known tumor suppressor gene. Analysis of non-hereditary cases of pancreatic cancer has identified approximately 100 genes where mutations have been associated with malignant transformation. These genes represent a variety of different functional groups, including cell cycle regulation, cytokines and growth factors, as well as cytokine and growth factor receptor genes.^4-6

Pancreatic cancer is the seventh most common cause of cancer deaths, resulting in 330,000 deaths worldwide.⁷ Pancreatic cancer is more common in the developed world and in the United States, it is the fourth most common cause of deaths due to cancer.⁸ Pancreatic adenocarcinoma typically has a poor prognosis: after diagnosis, 25% of people survive one year and only 5% live for five years.^7,9 There are approximately 46,000 cases of pancreatic cancer annually in the US and approximately 40,000 deaths.³ Pancreatic cancer is responsible for 6% of cancer deaths each year.⁸ and is the seventh highest cause of death from cancer worldwide. Globally, pancreatic cancer is the 11th most common cancer in women and the 12th most common in men.

Animal Models of Pancreatic Cancer

Pharma Models LLC offers a variety of different models of pancreatic cancer. Most often used are the sub-cutaneous human tumor xenografts, but most of the cell lines used in these models can also be implanted directly into the most common metastatic site for human pancreatic cancer – the liver.

Subcutaneous Xenograft Models for Human Pancreatic Cancer

There are several cell lines that are commonly used as subcutaneous xenografts for pancreatic cancer in immunocompromised mice. Several examples of typical growth curves are shown in Figure 1. In these examples, three pancreatic cancer cell lines were implanted subcutaneously in nude mice and the growth of the resulting tumors followed. In this model, treatment would typically begin at a mean tumor volume of 100 mm³, and continue until the negative control tumors reach a volume of 1500 mm³.

Figure 1: Representative Growth Curves for Three Pancreatic Cancer Cell Lines. Nude mice were implanted subcutaneously with 2×10⁶ cells on Day 0.

Orthotopic Models of Pancreatic Cancer

In addition to subcutaneous xenograft models of cancer, Pharma Models LLC has several luciferase expressing pancreatic cancer cell lines that can be implanted into the pancreas of mice as an orthotopic model of pancreatic cancer. An example of the growth of an orthotopic pancreatic cancer model is shown in Figure 2. Please contact us for more information on this model.

Figure 2: Orthotopic Human Pancreatic Cancer Model.
Human pancreatic cancer cells expressing luciferase were implanted into the pancreas of nude mice and visualized with D-luciferin 8, 15, 22 and 29 days post implantation.

Metastatic Models of Pancreatic Cancer

Metastatic cancer is of tremendous clinical importance, though often of less significance in pancreatic carcinoma due to the aggressive nature of the primary cancer. Animal models of metastatic cancer have traditionally been difficult to standardize and dependent on histological analysis, which is slow and relatively expensive. With the advent of in vivo imaging, and the availability of labeled cell lines, metastatic disease can be readily evaluated in vivo multiple times during the course of a study, allowing for the impact of treatment to be evaluated as the study progresses, and data to be collected and analyzed in real time, rather than long after the end of the study. Pancreatic carcinoma cells can be injected directly into the liver, allowing greater standardization and control over the growth of the tumor at the metastatic site. Pharma Models LLC has several pancreatic cancer cell lines that express luciferase and can be used to evaluate the treatment of metastatic pancreatic cancer in the liver (see Figure 3 for examples).

Figure 3: Metastatic Pancreatic Cancer in Liver. Human pancreatic cancer cells expressing luciferase were implanted intrahepatically into nude mice and visualized with D-luciferin 8, 15, 22 and 29 days post implantation.

Bibliography

1. Pancreatic Cancer Treatment (PDQ®) Patient Version. National Cancer Institute. National Institutes of Health.
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3. Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, Hruban RH. Recent progress in pancreatic cancer. CA: a Cancer Journal for Clinicians. 2013;63(5):318–48.
4. Hartley T, Cavallone L, Sabbaghian N, Silva-Smith R, Hamel N, Aleynikova O, Smith E, Hastings V, Pinto P, Tischkowitz M, Tomiak E, Foulkes WD. Mutation analysis of PALB2 in BRCA1 and BRCA2-negative pancreatic and/or ovarian cancer families from Eastern Ontario, Canada. Hereditary Cancer in Clinical Practice. 2014;12(1):19.
5. Potrony M, Puig-Butillé JA, Aguilera P, Badenas C, Carrera C, Malvehy J, Puig S. Increased prevalence of lung, pancreatic, and pancreatic cancers in addition to melanoma risk in families bearing the cyclin-dependent kinase inhibitor 2A mutation: Implications for genetic counseling. Journal of the American Academy of Dermatology. 2014;71(5):888-95.
6. Saiki Y, Horii A. Molecular pathology of pancreatic cancer. Pathol International. 2014; 64(1):10-9.
7. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. New England Journal of Medicine. 2014;371(11):1039–49.
8. American Cancer Society
9. Pancreatic Cancer Treatment (PDQ®) Health Professional Version. National Cancer Institute. National Institutes of Health.