Ancla 26, Marina VallartaPuerto Vallarta, Jal. Mx 48335
9:00 am - 4:00 pm CSTMonday - Friday
Chenwei Li, David G. Heidt, Piero Dalerba, Charles F. Burant, Lanjing Zhang, Volkan Adsay, Max Wicha, Michael F. Clarke and Diane M. Simeone
Departments of Surgery, Molecular and Integrative Physiology, and Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan; Department of Pathology, Karmanos Cancer Center, Detroit, Michigan; and Department of Internal Medicine, Stanford University School of Medicine, Palo Alto, California
Pancreatic adenocarcinoma is a highly lethal disease, which is usually diagnosed in an advanced state for which there are little or no effective therapies. It has the worst prognosis of any major malignancy (3% 5-year survival) and is the fourth most common cause of cancer death yearly in the United States, with an annual incidence rate approximating the annual death rate of 31,000 people. Despite advances in surgical and medical therapy, little effect has been made on the mortality rate of this disease. One of the major hallmarks of pancreatic cancer is its extensive local tumor invasion and early systemic dissemination. The molecular basis for these characteristics of pancreatic cancer is incompletely understood.
Attempts to better understand the molecular characteristics of pancreatic cancer have focused on studying gene and protein expression profiles of samples of pancreatic cancer. However, these types of studies have not taken into account the heterogeneity of cancer cells within a particular tumor. Emerging evidence has shown that the capacity of a tumor to grow and propagate is dependent on a small subset of cells. This concept was originally based on the observation that when cancer cells of many different types were assayed for their proliferative potential in various in vitro or in vivo assays, only a minority of cells showed extensive proliferation. This observation caused the idea that malignant tumors are composed of a small subset of distinct cancer stem cells (typically <5% of total tumor cells based on cell surface marker
expression), which have great proliferative potential, as well as more differentiated cancer cells, which have very limited proliferative potential.
The existence of cancer stem cells was first proven in the context of acute myelogenous leukemia (3, 4) and subsequently verified in breast and brain tumors. In 2003, Al-Hajj et al. reported that a phenotypically distinct and relatively rare population of CD44+CD24epithelial-specific antigen (ESA)+ tumor-initiating cells (TIC) was responsible for the propagation of human metastatic breast cancer specimens in immunodeficient nonobese diabetic (NOD)/severe combined immunodeficient (SCID) mice. Further evidence in support of a role for stem cells in solid tumors has also come recently from studies of brain tumors (6–8). Singh et al. showed that the neural stem cell antigen CD133 was expressed in brain-derived TICs from pediatric medulloblastomas and astrocytomas. The CD133+ subpopulations from these tumors
could initiate clonally derived neurospheres in vitro that showed self-renewal, differentiation, and proliferative characteristics similar to normal brain stem cells (6–8). Furthermore, transplantation of CD133+, but not CD133, cells into NOD/SCID mice was sufficient to induce growth of tumors in vivo. These cells have been termed cancer stem cells because, like normal stem cells, they can both self-renew and produce differentiated progeny. Recently, the identification of cancer stem cells has also been reported in human prostate and ovarian cancers. A practical consequence of this tumor cell heterogeneity is that strategies for inducing cell death must address the unique survival mechanisms of each different cell type within the malignant population. Most traditional cancer treatments have been developed and assayed based on their ability to kill most of the tumor population (i.e, log kill assays). However, these treatments can easily miss the cancer stem cells, which have been shown in several tumor types to be more resistant to standard chemotherapeutic agents. This model explains why standard chemotherapy may result in tumor shrinkage, but most tumors recur, likely because the cancer stem cell survives and regenerates the tumor. Treatments specifically targeting the cancer stem cell population may be more effective in resulting in solid tumor cure.
Stem Cell Clinical Research
Calle Ancla #26,
Puerto Vallarta, Jalisco
Tel: +52.322 222 6632