Herceptin targets breast cancer stem cells

July 9, 2008,

A gene that is overexpressed in 20 percent of breast cancers increases the number of cancer stem cells, the cells that fuel a tumor's growth and spread, according to a new study from the University of Michigan Comprehensive Cancer Center.

The gene, HER2, causes cancer stem cells to multiply and spread, explaining why HER2 has been linked to a more aggressive type of breast cancer and to metastatic disease, in which the cancer has spread beyond the breast, the researchers say.

Further, the drug Herceptin, which is used to treat HER2-positive breast cancer, was found to target and destroy the cancer stem cells. Results of the study appear online in the journal Oncogene.

"This work suggests that the reason drugs that target HER2, such as Herceptin and Lapatanib, are so effective in breast cancer is that they target the cancer stem cell population. This finding provides further evidence for the cancer stem cell hypothesis," says study author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center.

The cancer stem cell hypothesis says that tumors originate in a small number of cells, called cancer stem cells, and that these cells are responsible for fueling a tumor's growth. These cells represent fewer than 5 percent of the cells in a tumor. Wicha's lab was part of the team that first identified stem cells in human breast cancer in 2003.

In the current study, researchers found that breast cancer cells overexpressing the HER2 gene had four to five times more cancer stem cells, compared to HER2-negative cancers. In addition, the HER2-positive cells caused the cancer stem cells to invade surrounding tissue, suggesting that HER2 is driving the invasiveness and spread of cancer.

The researchers then looked at the drug Herceptin, which is used to treat HER2-positive breast cancer. They found Herceptin reduced the number of cancer stem cells in the HER2-positive breast cancer cell lines by 80 percent, dropping it to the same levels seen in HER2-negative cell lines.

When HER2 was not overexpressed in the cell cultures, the researchers found, the cancer stem cell population did not increase. Nor did Herceptin have any effect on the HER2-negative cells, which is consistent with how Herceptin is used in the clinic.

"We are now studying what pathways are activated by HER2 overexpression. Our hope is that we could develop inhibitors of these pathways that might be effective in targeting cancer stem cells in women whose tumors do not overexpress HER2 or those who are resistant to Herceptin," says study author Hasan Korkaya, Ph.D., a U-M research fellow in internal medicine.

Source: University of Michigan

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gdpawel
not rated yet Jul 13, 2008
Some patients' tumors respond to chemotherapy and some do not. A pathway/mechanism - cancer stem cells - may be the cause. To prevent cancer's return may require one therapy to shrink a tumor and another therapy to kill the abnormal seeds that sprouted it. Conventional cancer therapies have been good at shrinking tumors, but the ability to shrink tumors has little or no correlation to survival times. Newer treatments need to decrease the number of cancer stem cells.

There is a communication between stem cells and a tumor. It sends out a signal that make the different cells of the tumor and the cancer cells then (send chemical messages) that cycle back to the cancer stem cell. Every tissue and organ in the body is made of cells. In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific pathways that involve various genes and proteins in a cell.

Finding the protein that prevents cancer from metastasizing, isolating factors within the stem cell microenvironment, can influence tumor cell fate and reverse the cancerous properties of metastatic tumor cells. However, it is not the only tumor suppressive factor within the stem cell microenvironment. Not all genes and proteins have a critical role in the survival and growth of cancer cells.

In some cases, targeted drugs may kill tumor cells without killing microvascular cells in the same time frame. In other cases, they may kill microvascular cells without killing tumor cells. Yet in other cases, they could kill both types of cells or neither type of cells. The ability to these targeted agents to kill tumor and/or microvascular cells in the same tumor is highly variable among the different agents.

You still need to measure the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific cancer drugs, not just the individual molecular targets. Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease.

Sources:
Cell Function Analysis
European Science Foundation
American Association for Cancer Research

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