Human pancreatic cancer stem cells: implications for how we treat pancreatic cancer

Abstract

Pancreatic cancer has the worst prognosis of any major malignancy, with an annual death rate that approximates the annual incidence rate. Delayed diagnosis, relative chemotherapy and radiation resistance and an intrinsic biologic aggressiveness all contribute to the abysmal prognosis associated with pancreatic cancer. Answers to the frustrating effort to find effective therapies for pancreatic cancer may be gained through a renewed perspective on tumorigenesis as a process governed by a select population of cells, termed cancer stem cells (CSCs). Cancer stem cells, like their normal counterparts, have the properties of self-renewal and multilineage differentiation and possess inherently heightened DNA damage response and repair mechanisms that make them difficult to eradicate. Initially discovered in leukemias, researchers have identified CSCs in several solid-organ malignancies including breast, brain, prostate, and colon cancers. We have recently identified a CSC population in human pancreatic cancers. These pancreatic CSC represent 0.5% to 1.0% of all pancreatic cancer cells and express the cell surface markers CD44, CD24, and epithelial-specific antigen. Pancreatic CSCs have been shown to be resistant to standard chemotherapy and radiation, and devising specific therapies to target this distinct cell population is likely needed to identify effective therapies to treat this dismal disease.

Figure 1

Tumor formation in NOD-SCID mice injected with pancreatic cancer stem cells. Implantation of 500 CD44⁺CD24⁺ESA⁺ pancreatic CSCs results in tumor formation (top panel). Expression of the proteins S100P (middle two panels) and stratifin (bottom two panels) is similar in the tumor generated from CD44⁺CD24⁺ESA⁺ cells and the patient's primary tumor.

Figure 2

Upregulation of developmental signaling molecules in pancreatic CSCs. mRNA expression of SHH (A) and BMI-1 (B) in normal pancreas, nontumorigenic CD44^-CD24^-ESA^- pancreatic cancer cells, and highly tumorigenic CD44⁺CD24⁺ESA⁺ pancreatic CSCs. Total RNA was quantitated by real-time reverse transcription-polymerase chain reaction. Data are expressed as the mean ± SE. *P < .05 versus normal pancreas.