Pancreatic cancer metastasis: are we being pre-EMTed?

Abstract

Pancreatic cancer, often considered a metastatic disease at the time of clinical diagnosis due to lack of any reliable early diagnostic marker(s), is refractory to conventional chemo- and radiotherapy and has a dismal 5-year survival rate of only 6%. Although surgical removal of the primary tumor is considered to be curative, the 5-year survival rate is no more than 20% even in patients with clear resection margins (R0). The recurrence of local and metastatic disease (primarily liver metastasis) post resection is considered to be the leading cause of mortality in these patients. In addition, instances of metastatic disease without any local recurrence post resection have also been observed. Cancer metastasis is the primary cause of mortality in cancer patients and is classically viewed as a late event during the progression of the disease, which is supported by the genetic studies used to understand the evolution of pancreatic cancer. However, this view has recently been challenged by studies using mathematical modeling and genetically labeled mouse models of pancreatic cancer to understand the dynamics of tumor cell dissemination and epithelial to mesenchymal transition (EMT) of tumor cells well before the primary tumor is formed. Given that EMT is a hallmark process that initiates the metastatic seeding of cancer cells and the dismal prognosis of pancreatic cancer patients even after efficient removal of the primary tumor (99.9%), an early dissemination hypothesis of cancer cells cannot be undermined. In this review, we will discuss the current views regarding pancreatic cancer metastasis with particular emphasis on the epithelial to mesenchymal transition, its influence on the selection of patients for surgical resection and the therapeutic intervention.

Fig. 1. Late dissemination (linear progression) and early dissemination (parallel progression) model of pancreatic cancer metastasis

Pancreatic cancer progression model is depicted inside the pancreas. Normal pancreatic epithelial cells (N) by acquiring several genetic alterations (primarily K-RAS, p16^INK4A, SMAD4 and p53) progress through a step-wise histological abnormality characterized by columnar epithelial cells with a gradual increase in nuclear atypia, loss of polarity, nuclear crowding and hyperchromasia and pseudostratification known as pancreatic intra epithelial neoplasia (PanIN-1A, 1B, 2 & 3) and finally culminating in pancreatic ductal adenocarcinoma (PDAC). Late dissemination model: Proponents of the late dissemination (also known as linear progression) model suggest it takes >10 years for the non-metastatic primary tumor to be formed from the time of the initiating mutation followed by another 5–6 years for the development of metastatic subclones (red dotted arrows). According to this model, pancreatic cancer metastasis is a late event, and this presents with a window of opportunity of more than 10 years to catch the disease early. Once the metastatic subclones are developed, it takes another 2–3 years to develop the metastatic disease, which ultimately kills the patient. Early dissemination model: On the other hand, proponents of early dissemination model (also known as parallel progression model) suggest tumor cells as early as PanIN-2 lesions (brown colored cells) activate the epithelial to mesenchymal transition (EMT) program, invade the basement membrane, enter the systemic circulation and seed at anatomically distant organ site(s) (blue dotted arrows). Although these solitary cells have been seen only in the liver, they could be present any organ (Lungs, Peritoneum, Diaphragm etc.) where pancreatic cancer metastasizes. At this point, experimental validation is lacking for the cells that disseminated from early precancerous state for metastatic colonization. Besides, the kinetics of this dissemination is also unknown.