Two Studies Identify Drivers of Metastases

A study published in the January 10 Nature has pinpointed several microRNAs (miRNAs) - tiny RNA strands that regulate gene expression - that help suppress breast cancer metastases.

Researchers from Memorial Sloan-Kettering Cancer Center examined miRNAs in breast cancer cell lines that were highly metastatic to bone and lung compared with control breast cancer cell lines. They chose to focus further studies on the six miRNAs whose expression was most decreased in the metastatic cells.

Restoring the function of three of these miRNAs - called miR-335, miR-206, and miR-126 - by gene therapy significantly reduced the formation of bone metastases in mice implanted with the breast cancer cell lines. Rare cells that did metastasize had decreased expression of the three miRNAs.

To measure the expression of these miRNAs in human tumors, the investigators used archived tissue samples from 11 women with metastatic breast cancer and 9 women whose cancer did not metastasize. They found that patients whose primary tumors had low expression of the three miRNAs "had a shorter median time to metastatic relapse."

In particular, low levels of miR-335 or miR-126 "were associated with very poor overall metastasis-free survival compared to the group whose tumors expressed a high level of these miRNAs." Further studies identified genes regulated by miR-335 that are directly associated with relapse.

A second study published in the January 11 Science identified a specific contribution of cells in the tumor microenvironment involved in the angiogenic switch - the generation of a tumor blood supply - and the associated progression of lung micrometastases to deadly macrometastases.

Researchers from Cold Spring Harbor Laboratory found that micrometastases that recruit a type of cell called a bone marrow-derived endothelial progenitor cell (EPC) to their immature blood vessels undergo development of a blood supply, in both xenograft and spontaneous mouse models of cancer.

The researchers also identified a protein called Id1 that is needed to draw the EPCs to the tumor site. When this protein was suppressed in a mouse model, the number of EPCs in the bloodstream was significantly reduced, and tumor blood vessel growth was suppressed. "These findings …suggest that the efficacy of antiangiogenic inhibitors used in clinical trials…may be a consequence of directly targeting [bone marrow]-derived EPCs, as well as the nascent tumor vasculature," conclude the authors.

Black British Women Younger at Breast Cancer Diagnosis

In the first published study of patterns of breast cancer in British black women, available online January 8 in the British Journal of Cancer, researchers found that black women were diagnosed with invasive breast cancer at a significantly younger median age than white women and had a higher frequency of higher grade tumors, estrogen receptor (ER)-negative, and basal-like (triple negative) tumors, similar to African American women.

The investigators from Cancer Research UK identified 102 black women and 191 white women diagnosed with invasive breast cancer between 1994 and 2005 at a hospital in East London. Black patients were diagnosed at a median age of 46, compared with a median age of 67 for white patients. An analysis of the population structures in the geographical area showed no differences between the black and white populations, "confirming that there is a true increase in the frequency of breast cancer in young black women."

Black patients also had a greater frequency of grade 3 tumors, positive lymph nodes, and ER-negative, progesterone receptor-negative, and basal-like tumors; however, only tumor grade was significantly different in all age groups. None of the results changed when adjusted for socioeconomic status.

No significant difference in overall survival was found between black patients and white patients. However, for women whose tumors were 2 centimeters in size or smaller, black patients had poorer survival. Because records showed that black women received more adjuvant therapy than white women, the authors conclude that "there is no evidence that observed differences are due to…inequalities in the receipt of therapy."

The current government breast cancer screening program in the United Kingdom begins at age 50. The authors suggest that "alterations to the screening services offered to black populations might be considered to better reflect the incidence patterns for this group."

Melanoma Study Finds, Targets Tumor Stem Cells

Researchers several years ago identified a population of cells within melanoma skin cancers that may cause resistance to chemotherapy. The researchers now say that these cells, which express the protein ABCB5, may be uniquely suited to initiate tumors and fuel their growth. Dr. Markus Frank of Harvard Medical School and his colleagues report in the January 17 Nature that antibodies against this protein can help prevent tumors from developing in animal models of the disease.

The study describes a hierarchy of cells within melanoma tumors. The capacity to self-renew and give rise to diverse cell types - the hallmarks of tissue stem cells - are concentrated in the ABCB5-positive cells, the researchers conclude. An analysis of tumors revealed greater expression of ABCB5 in more clinically advanced cases compared to less advanced cases, suggesting a link between these cells and melanoma progression.

The cancer stem cell hypothesis says that some cancers are driven by small populations of self-renewing cells. The cells have been reported in various tumor types, including brain, breast, and pancreatic tumors. Previous reports on melanoma have proposed that the proteins CD133 and CD20 may be markers of tumor stem cells.

Few studies have tested the idea that patients would benefit from the eradication of tumor stem cells. Support now comes from experiments in this study showing that antibodies against ABCB5-positive cells inhibited tumors in mice.

"This study provides validation of the hypothesis that specifically targeting cancer stem cells would inhibit tumor growth," said Dr. Frank, noting that more research is needed before the strategy could be applied to humans. Additional markers to further characterize melanoma stem cells at the clonal level are also needed because not every ABCB5-positive cell is a tumor-initiating cell.

Brain Tumor Stem Cells May Depend on Silenced Gene

Researchers have identified a gene that is improperly silenced during the development of some neural stem-like cells in vitro, a finding which could help explain why similar cells may result in aggressive brain tumors in vivo. Further experiments in a human line derived from cells taken from glioblastoma multiforme patients showed that activating the silenced gene restores its normal developmental stages, suggesting a potential strategy for treating patients.

Tumor stem-like cells, like normal stem cells, can self-renew, but unlike stem cells, they fail to differentiate into normal cell types. Instead, they give rise to dysregulated cells, which may develop into a tumor.

This new research links changes in gene regulation to the survival of stem-like cells in culture and exposes a possible Achilles' heel.

Lead investigator Dr. Howard Fine of NCI's Center for Cancer Research is collaborating with drug developers to identify compounds that could activate the silenced gene in the subset of glioblastoma brain cancers with a similar flaw. The hope is that causing neural stem-like cells to mature could stop them from developing into brain tumors.

As reported in the January Cancer Cell, the silenced gene is the bone-morphogenetic protein receptor 1B (BMPR1B), which is involved in cell differentiation. The silencing occurs through an epigenetic change known as methylation in which the gene is chemically modified.

A surprise was that even though the brain cancer stem-like cells had genetic flaws as well as the epigenetic change, the single step of reactivating the BMPR1B receptor caused the cells to grow and differentiate normally. "We may be able to use a drug to differentiate these tumor stem cells without having to treat all the other genetic abnormalities," noted Dr. Fine. "One could argue that the stem-like cell pathways may trump the classic oncogenic pathways."

The findings also suggest that all cancer stem-like cells do not have the same flaws. Rather, to treat the disease it may be necessary to identify the specific pathways that are disrupted in individual cancer cells. The researchers estimate that the BMPR1B gene is silenced in 15 to 20 percent of glioblastoma cases.

Newly Discovered Virus Linked to Aggressive Skin Cancer

Researchers have identified a previously unknown virus and linked it to Merkel cell carcinoma, a rare but usually rapidly fatal skin cancer. The researchers, led by Drs. Yuan Chang and Patrick Moore of the University of Pittsburgh Cancer Institute, say it is too soon to know whether the virus causes the cancer, but their evidence suggests that it may be a contributing factor.

The virus, which they named Merkel cell polyomavirus (MCV), was reported in Science on January 17. It is related to a group of polyomaviruses, which has long been known to cause cancer in animals.

Merkel cell carcinoma has been linked to sun exposure and a weakened immune system, though its causes are not known. Approximately 1,500 cases are diagnosed in the U.S. each year. The incidence has been rising, particularly among individuals whose immune systems are compromised by AIDS or immunosuppressant drugs.

The researchers detected MCV DNA in 8 of 10 Merkel cell tumors they tested. By comparison, it was found in 5 of 59 (8 percent) control tissues from various body sites and 4 of 25 (16 percent) control skin tissues. It is not clear why most - but not all - Merkel cell tumors are infected with the virus.

Experiments indicated that the virus had infected human cells before the cells became malignant. In addition, the viral DNA was integrated in six of the eight tumors. This suggests that the virus plays a role in the tumor, the researchers note on a Web site describing the findings. They used a technique called digital transcriptome subtraction to isolate a viral DNA sequence that was similar to but distinct from all known viruses.

If MCV is shown to play a role in the cancer, investigators will have new leads to explore for understanding and treating the deadly disease. The discovery could have implications for other cancers, noted Dr. Kishor Bhatia of NCI's Center for Cancer Research.

In 1994, Drs. Moore and Chang discovered the virus that causes Kaposi sarcoma, the most common malignancy in AIDS patients and the most common cancer in Africa.

Comorbidities May Limit Benefits of Combination Prostate Therapy

The addition of androgen suppression therapy (AST) to radiation therapy (RT) improved overall survival in men with localized prostate cancer and risk factors for disease recurrence, but the survival benefit may apply only to men who do not have moderate to high levels of other illnesses, researchers report in the January 23 Journal of the American Medical Association.

Previous observational studies and pooled analyses of randomized trials have suggested that AST may be associated with an increased risk of heart attacks and other cardiovascular events in older men.

In the current study, researchers randomly assigned 206 men with localized prostate cancer and a high risk of recurrence to either RT alone or RT plus AST for 6 months. The men, whose average age was 72.5, were classified into subgroups based on the severity of their other illnesses, such as diabetes or a previous heart attack.

After 7.6 years median follow-up, estimated 8-year survival was 74 percent for men randomized to RT plus AST compared with 61 percent for men assigned to RT alone. A total of 74 men had died - 44 of those assigned to RT alone and 30 assigned to RT plus AST.

Among the 157 men with only minor comorbidities, 31 of those treated with RT alone had died, compared with 11 of those in the RT plus AST group. Among the 49 men with moderate to severe comorbidities, however, 19 of those randomized to RT plus AST had died, compared with 13 of those assigned to RT alone.

"Preexisting comorbid illness may increase the negative effects of specific anticancer treatments such as AST," conclude the researchers, who were led by Dr. Anthony V. D'Amico of Brigham and Women's Hospital in Boston. They recommend that follow-up clinical trials be designed to further assess this interaction and identify which illnesses in particular may shorten life expectancy among men undergoing treatment with AST.