Primary pancreatic tumorResearchers at the University of Michigan Medical Center have, for the first time, identified human pancreatic cancer stem cells. Their work indicates that these cells are likely responsible for the aggressive tumor growth, progression, and metastasis that define this deadly cancer.
In the February 1 issue of Cancer Research, the researchers demonstrate that only 100 of these stem cells are needed to produce human pancreatic cancer in half of mice tested. They also found these cells are at least 100 times more tumorigenic than cancer cells that did not have one of three protein markers they believe to be associated with pancreatic cancer stem cells.
Cancer stem cells are the small number of cancer cells that replicate to drive tumor growth. Researchers believe current cancer treatments sometimes fail because they are not attacking the cancer stem cells. By identifying the stem cells, researchers can then develop drugs to target and kill these cells.
Pancreatic cancer has a five-year survival rate of only three percent - the worst prognosis of any major cancer, said the study's lead author, Diane M. Simeone, M.D., an associate professor of surgery and molecular and integrative physiology.
Pancreatic tumor generated from stem cells The study also advances the emerging notion that stem cells may lie at the heart of some, if not all, cancers, Simeone said. That theory suggests that only cells that have the properties of "stemness"- that is, cells that can self-renew and differentiate into other types of cells - are the only ones capable of producing tumors. These "cancer stem cells," could derive from normal adult stem cells in organs that have mutated, or from a differentiated cell that has devolved to take on the qualities of stem cells. They are resistant to traditional therapy designed for cells that rapidly turn over because stem cells don't, according to some researchers. Thus, they remain after tumors shrink and may be responsible for cancer recurrence and metastasis.
To look for cancer stem cells in pancreatic cancer, the research team implanted cancerous tissue from human pancreatic specimens removed during patient surgery in "xenograft" mice with compromised immune systems. Researchers removed tumors after they grew, and then sorted millions of cancer cells to isolate those that had one or more of three surface protein markers - CD44, CD24, and ESA. They chose these markers, called cell adhesion molecules, because they'd recently been found on isolated breast cancer cells by study co-authors Max Wicha, M.D., from Michigan and Michael Clarke, Ph.D., from Stanford University School of Medicine.
The researchers then implanted about 100 of each type of cell in mice, and found that tumors would grow in a subset of the animals, but cells that expressed all three markers were the most potent, producing tumors in six of 12 mice tested. If more cells are used, "we can get tumors to grow 100 percent of the time," Simeone said. "These cells are highly tumorigenic, which reflects the biology of this cancer."
Additionally, the tumors derived from the highly tumorigenic pancreatic cancer cells "appeared remarkably similar to the appearance of tumors taken directly from patients," Simeone said. The purported cancer stem cells produced a diverse mixture of cells, some of which are not cancerous, that reflected an actual human pancreatic tumor, she said.
The markers that define the highly aggressive pancreatic cancer subtype are not identically matched to those found in aggressive breast cancer, the researchers also discovered. The difference is in one marker, CD24, which is negative in breast cancer and positive in pancreatic cancer, according to Simeone.
Stem cells have been identified in several other cancer types, including breast, brain, central nervous system and colon cancers, as well as leukemia. U-M researchers in 2003 were the first to report the existence of stem cells in a solid tumor, finding them in breast cancer. CD44, CD24 and ESA were also found to play a role in breast cancer stem cells. A study published in January 2007 by U-M and Stanford University researchers narrowed the field for head and neck cancer stem cells, again finding that cells expressing CD44 were involved.
Researchers suggest that a small subpopulation of cancer cells are the critical cells in cancer growth and progression, and the key to treating cancer is to kill these stem cells. It’s a radically different model than current treatment approaches, which are designed to shrink the tumor by killing as many cells as possible. Researchers suspect cancer recurs because the treatments are not killing the stem cells.
“The current model may lead to treatments limited in their effectiveness, because we have not been targeting the most important cells in the tumor – the cancer stem cells. If we hope to cure more cancers we will need to target and eliminate this critical type of cancer cell,” says study author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center.
"With this finding in pancreatic cancer, we can now define what we believe are the important cells – the cells that determine whether the cancer will come back or be cured – and target treatment directly to those cells," says Wicha, who was part of the team that discovered stem cells in breast cancer.
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