Recent discoveries about the role of stem cells in cancer have altered the landscape of cancer research. With each new study, scientists are learning more about cancer-initiating properties of stem cells at organ sites and throughout the body.
Increasingly stem cells are examined as the cause and potential target of treatment for many if not all cancers. At the 2007 Annual Meeting of the American Association for Cancer Research, researchers present new discoveries about stem cells in leukemia, breast and colon cancer that add to the growing evidence that perhaps cancer is, fundamentally, a stem cell problem.
PTEN and HER2 regulate self-renewal and invasion of human mammary stem cells: Abstract 1287
Two genes associated with aggressive breast cancer are linked to a key property of mammary stem cell function, according to researchers at the University of Michigan. The genes, PTEN and HER2, both are involved in the biochemical pathways that mediate stem cell self-renewal, a defining property of stem cells.
According to the researchers, understanding the pathways that regulate stem cell self-renewal is important in developing therapeutics that target the tumor stem cell pool. These genes might also become targets of interest in the treatment of tumors resistant to the drug Herceptin.
"We now believe that our results show further evidence that breast cancer arises from signaling errors in the biochemical pathways that control mammary stem cell self-renewal" said Hasan Korkaya, D.V.M., Ph.D., a research fellow at the University of Michigan's Comprehensive Cancer Center. "Since only stem cells have the ability to self-renew, deregulation of either PTEN or HER2 expands the stem cell populations with self-renewing ability."
According to Korkaya, cells with deregulated , or increased , self-renewing ability will then initiate and maintain tumors that are resistant to current therapies.
The two genes appear to influence stem cell self-renewal by controlling two different arms of the pathway, says Korkaya. In breast cancer, the loss of PTEN is linked to nearly a quarter of all cases, while the overproduction of HER2 is associated with nearly 40 percent of all cases. Patients with a combined defect of PTEN loss and HER2 amplification represent worse prognosis than either defect alone.
To replicate this clinical phenomenon and study the link between stem cell self-renewal and tumorigenesis, the researchers altered the expression of the two genes in a line of human breast carcinoma cells. In experimental settings, their results confirmed this clinical data that either defect increases stem cell population by three to five times. Furthermore, Korkaya observed an additive effect and an approximate 10-fold increase in stem cell population when they created a cell line with deleted PTEN and HER2 overexpression. Another property of aggressive tumors is metastasis; the team also found that these cells had increased invasive capacity in a matrigel invasion assay.
"In general, tumors are heterogeneous including stem and non-stem cell populations in a given malignancy," Korkaya said. "If the stem cells acquired mutations in their self-renewing pathways, they will then begin reproducing at an accelerated rate, leading to a particularly aggressive form of cancer."
The researchers believe further studies will identify new biomarkers that will enable physicians to clinically screen patients for mammary stem cells and provide specific treatments designed to target these cells.
Local Radiotherapy Might Contribute to Leukemia Risk in Breast Cancer by Recruitment of Hematopoietic Stem Cells: Abstract 5050
Radiation therapy affects not only the cancer mass, but also the surrounding tissues, including the bone marrow. Signals from the cells in the bone marrow damaged by cancer radiotherapy could be involved in the development of secondary acute myeloma by drawing hematopoietic stem cells, the blood-producing cells of the bone marrow, from distant sites into the irradiated bone marrow, according to researchers from the Ontario Cancer Institute. Their findings suggest that local radiotherapy leads to leukemia, even though radiotherapy directly affects only a small fraction of the bone marrow.
While often effective in treating breast cancer, localized radiation therapy increases the risk of developing secondary cancer, which most frequently manifests in the form of acute myeloid leukemia. In breast cancer, less than 10 percent of bone marrow is exposed to radiation therapy, yet a much higher percentage of hematopoietic stem cells could be affected.
To understand this effect, the researchers labeled and tracked the movement of hematopoietic stem cells in an animal model. Following local radiation therapy, they found that more than four times more hematopoietic stem cells accumulated in the irradiated bone marrow, compared to the non-irradiated bone marrow. Through molecular screening, they found that cells in the area were creating an overabundance of three protein signals known to recruit hematopoietic stem cells: SDF1, MMP2 and MMP9.
"Cells within the bone marrow send out these chemical signals as a sort of call for help, which recruits a large number of hematopoietic stem cells into the affected areas, supposedly to replace damaged cells," said Carlo Bastianutto, Ph.D., a scientific associate at the Ontario Cancer Institute. "In effect, this becomes a trap for this specific population of stem cells, drawing them into the bone marrow present in the radiation field and getting them exposed to the following radiation cycles. This story might repeat at every cycle of radiation therapy, therefore increasing the chance of producing a leukemic stem cell."
According to the OCI researchers, the recruiting signal might be stopped by chemical blockers, which was shown to inhibit the signals experimentally. "Conceivably, it could be possible to inhibit these chemical signals, and this could reduce the risk of secondary acute myeloid leukemia, but much more research needs to be done," Bastianutto said.
The researchers believe this model could help prevent acute myeloid leukemia in patients with malignancies other than breast cancer.
Prospective identification of highly tumorigenic colon adenocarcinoma cells enriched for stem-like properties: Abstract 1288
Colon cancer could join the growing list of stem cell-related cancers with the discovery of a population of highly tumorigenic primary human colon tumor cells, according to researchers from Biogen Idec.