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Whitehead Develops Improved Method to Produce Human Breast Cancer ‘Stem Cells’

Researchers at the Whitehead Institute for Biomedical Research have developed a method for producing breast cancer “stem cells” that can be used to generate a much larger number of tumor cells for research uses than previous approaches.
The method offers “a bountiful source” of cancer cells, according to Robert Weinberg, a professor of biology at MIT who led the research team that developed the procedure. “Labs can easily grow the newly created cells for use in experiments.”
The method is based on a new culture medium that enables the growth of a type of breast cancer cell that normally dies in culture. The team genetically transformed these cells into cancer cells, and found that as few as 100 of the cells successfully seeded tumors in mice, and those tumors metastasized.  
Current cancer cell lines require around a million cells to seed a tumor.
In the study, published in the August issue of Cancer Cell, Tan Ince, a pathologist in Weinberg’s lab, compared tumors derived from two different populations of normal human mammary epithelial cells. One cell population was isolated using a serum-free, chemically-defined medium that Ince developed called WIT.
Transformation of these two genetically equivalent cell populations produced cells that formed tumor xenografts exhibiting major differences in histopathology, tumorigenicity, and metastatic capability. One cell type — human mammary epithelial cells, or HMECs — produced squamous cell carcinomas, while the other type — breast primary epithelial cells, or BPECs — produced tumors closely resembling human breast adenocarcinomas. BPECs gave rise to lung metastases and were as much as 10,000 times more tumorigenic than the transformed HMECs, which were nonmetastatic.
The researchers concluded that tumor cell phenotype, including metastatic capability, can be strongly influenced by the cell phenotype that serves as the tumor cell precursor.
Cell-Based Assay News spoke to Weinberg this week about the work and the importance of tumor-initiating cells to the metastatic ability of tumors.
Can you give me a little background on your work?
Tan Ince, the lead author of the Cancer Cell paper, was interested in developing an alternative method of propagating human mammary epithelial cells in culture. He developed a new growth medium for doing so called WIT.
He transformed the mammary epithelial cells from a normal to a cancerous state. He then discovered that these cells more closely resembled in their appearance under the microscope the tumors that one routinely encounters in the oncology clinic.
Most interestingly, when we examined these tumors, we found them to have a high proportion of tumor-initiating cells, or cancer “stem cells.” What Ince found was that if he took as few as 100 of these transformed cells that he had created and injected them into a host mouse, they in fact formed a new tumor.
The standard practice is to take 100,000 to 1,000,000 of these cells to seed a new tumor. Therefore, this preparation of transformed cells that he made had a far higher percentage of tumor-initiating cells.
We do not really understand why there is such an enrichment for the tumor-initiating cells. It is possible that at least 10 percent of the cancer cells in the preparation are tumor-initiating cells. To be more conservative, we are saying that one in 100 cells are tumor-initiating cells.
The fact is that when you take breast cancer cells out of a human tumor and you quantitate the percentage of tumor-initiating cells, it could be as low as one in 10,000, one in 100,000, or even one in 1,000,000.
The problem is that if we want to understand tumor-initiating cells, such as breast cancer tumor-initiating cells, we need to make large numbers of them to study them in isolation, because they comprise such a minute percentage of the total tumor cells in a population.            
Many previously believed that all the cancer cells in a tumor were biologically equivalent to one another, and could seed a new tumor if transplanted into a mouse. The probability of it succeeding in forming a tumor may have very low, but they were all assumed to be biologically equivalent.
Over the last three to four years, researchers have found that a hierarchy of cells exists within a tumor. A minute proportion of tumor cells are capable of self-renewal, like most stem cells, and are also capable of seeding a new tumor, whereas a great majority of cancer cells, which are genetically identical to the tumor-initiating cells, are incapable of seeding a new tumor.  
This is analogous to the situation in normal, healthy tissue, which contains a small percentage of self-renewing stem cells and a large percentage of cells that carry out the work of the organ, but which have a limited proliferative capability.
We are now beginning to see a similar situation in a tumor, where a great majority of cells in the tumor, although they are malignant, actually have a limited ability to proliferate. They may grow several rounds, or perhaps five or ten doublings, but then they stop growing.
In contrast, the small number of tumor-initiating cells in a tumor appear to have an unlimited proliferative capability and seem capable of spawning the bulk of the population of cancer cells within a tumor.
You may ask the question, “Why are tumor-initiating cells so interesting?” It seems to be the case that tumor-initiating cells are more resistant to chemotherapeutic treatment than are the bulk of the cells in a tumor. That greatly complicates our thinking about how to treat tumors.
In the past, when we treated tumors with chemotherapy and we saw the bulk of the tumor disappear, it was celebrated as a great victory. However, if the tumor-initiating cells remain untouched by chemotherapy, then the ability of the tumor to metastasize is unaffected.
So the criteria that have traditionally been used to gauge the success of chemotherapeutic regimens, namely a reduction in tumor size, turns out to be an illusion in terms of explaining whether or not a given chemotherapeutic agent is or is not effective.
What one will need to do in the future is examine the extent to which the tumor-initiating cells in a tumor have been wiped out, because if they are wiped out, the tumor irrevocably loses its ability to metastasize. 
What findings reported in the paper did you feel were the most interesting?
Tumor-initiating cells are now, in principle, isolatable by researchers who are interested in studying a pure population of tumor-initiating cells, which has in the past proven to be very difficult because they are so rare.
The enrichment of the tumor cell population for tumor-initiating cells was not an intended outcome of this work. The intended outcome was to make a better laboratory model of human breast cancer.
What is the difference between Ince’s WIT media and other, standard cell culture media?
Some ingredients were increased and others deleted. It’s a complicated witches’ brew of 30 or 40 different things.  
Are these stem cells or the WIT media something that your lab or Ince may want to commercialize?
I do not think so. That has not been discussed.
What questions do you think could be addressed in future research?
The next step would be to generate large, pure populations of tumor-initiating cells.

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