Some Mesenchymal Stem Cells Inhibit Tumor Growth But Other Types of Mesenchymal Stem Cells Enhance Tumor Growth and Metastasis

Mesenchymal stem cells (MSCs) have the ability to home to growing tumors, and for this reason, many researchers have examined the possibility of using MSCs to treat various types of cancers. However, there is a genuine safety concern with using MSCs in cancer patients, because in laboratory animals, MSCs can form blood vessels that help tumors grow and spread. Consider the following publications:

1. Klopp AH, Gupta A, Spaeth E, Andreeff M, Marini F 3rd (2011) Concise review: Dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells 29: 11–19.
2. Kidd S, Spaeth E, Klopp A, Andreeff M, Hall B, et al. (2008) The (in) auspicious role of mesenchymal stromal cells in cancer: be it friend or foe. Cytotherapy 10: 657–667.
3. Coffelt SB, Marini FC, Watson K, Zwezdaryk KJ, Dembinski JL, et al. (2009) The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells. Proc Natl Acad Sci U S A 106: 3806–3811.
4. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, et al. (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449: 557–563.

Because MSCs are multipotental (that is they differentiate into several different adult tissues), they can serve the tumor as a source of blood vessels that augment tumor metastasis and growth. However, several pre-clinical studies with genetically engineered MSCs that deliver chemotherapuetic agents to tumors have proven quite successful (see Waterman RS, Betancourt AM (2012) The role of mesenchymal stem cells in the tumor microenvironment: InTech). So what are we to believe? After MSCs good or bad as tumor treatments?

In 2010, Aline M. Betancourt and colleagues at Tulane University, New Orleans, Louisiana defined two distinct MSC subypes in a MSC population. They referred to these subtypes as MSC1 and MSC2. When challenged with molecules normally found in invading microorganisms, MSC1 populations tend to promote the immune response, where as MSC2 populations tend to suppress the immune response. This simple priming experiment provided a way to distinguish between the two MSC subtypes, but it also gave stem cell scientists a reason why experiments with MSCs tend to give conflicting results in different laboratories – because the two labs were probably working with populations that consisted of different MSC subtypes. See Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM (2010) A New Mesenchymal Stem Cell (MSC) Paradigm: Polarization into a Pro-Inflammatory MSC1 or an Immunosuppressive MSC2 Phenotype. PLoS ONE 5(4): e10088. doi:10.1371/journal.pone.0010088.

With this in mind, Betancourt and co-workers examined the ability of the distinct MSC subtypes to interact with cancers. When grown in culture with several different types of tumor-causing cell lines, they discovered that MSC1 do not support tumor growth but MSC2 robustly support tumors growth. MSC2 also increased the ability of the tumors to invade other tissues and migrate in culture whereas MSC1 supported neither tumor invasion nor tumor migration.

Other features were different as well. For example, MSC1 recruited a completely different cadre of white blood cells to the tumor when compared to MSC2. Also, the molecules deposited in the vicinity of the tumor by MSC1 and MSC2 differed greatly. By providing a bed of molecules upon which tumors cell like to move and grow, MSC2s promoted tumor cell activity, but the materials laid down by MSC1 were not nearly as attractive to the tumor cells.

These show why MSCs can promote the growth of particular tumors in some experiments but not others. Furthermore, it shows that there is a relatively simple test to separate these two MSC subtypes. All further pre-clinical experiments with MSCs, should account for these distinct MSC subtypes and determine if one MSC subtype is a better candidate for an anticancer treatment regime than the other.

See Waterman RS, Henkle SL, Betancourt AM (2012) Mesenchymal Stem Cell 1 (MSC1)-Based Therapy Attenuates Tumor Growth Whereas MSC2-Treatment Promotes Tumor Growth and Metastasis. PLoS ONE 7(9): e45590. doi:10.1371/journal.pone.0045590.

Smart Bomb-Type Drug Successfully Treats Advanced Breast Cancer in Clinical Trials

In a key clinical trial with 1,000 women who had advanced breast cancer, the efficacy of an experimental treatment for breast cancer has been examined in some detail. This breast cancer treatment is one of the first “smart bomb” treatments for breast cancer.

This treatment uses a drug to deliver a toxic payload to tumor cells that also leaves the healthy cells alone. In this treatment, woman with advanced disease this experimental “smart bomb” treatment extended the lives of these sick women by several months, and during this time, the women lived without their cancer getting worse. After two years, 65 percent of women who received this treatment were still alive versus 47 percent of those in a comparison group who were given two standard cancer drugs. The developers of this treatment plan to report on it at a cancer conference in Chicago.

“The absolute difference is greater than one year in how long these people live,” said the study’s leader, Dr. Kimberly Blackwell of Duke University. “This is a major step forward.”

How does this treatment work? It builds on the cancer drug, Herceptin. Herceptin was developed as a gene-targeted therapy for breast cancer. In fact, it was the first gene-targeted treatment ever developed. Herceptin is used for about 20 percent of patients whose tumors overproduce a certain protein. Herceptin is the trade name for the drug trastuzumab, and this drug is a monoclonal antibody. Trastuzumab binds to a protein called “human epidermal growth factor receptor 2” or Her2. Her2 has several other names (Neu, ErbB2, CD340 or p185), but whatever you call it, Her2 binds a small protein called epidermal growth factor (EGF). The binding of EGF to Her2 sets a series of events into action inside the cell that causes it to grow and divide vigorously.

Her2 is overexpressed in breast cancer cells and the excessive signaling to the cell interior drives the breast cancer cells to grow faster and faster. Trastuzumab binds to Her2 and shuts the signaling that emanates from it down. Trastazumab is used as part of a treatment regimen that includes drugs like Adriamycin® (doxorubicin), Cytoxan® (cyclophosphamide), and either Taxol® (paclitaxel) or Taxotere® (docetaxel). Such a treatment course is known as “AC→TH.” Other treatment regimens include Herceptin with Taxotere and Paraplatin® (carboplatin). This treatment course is known as “TCH.”

In this “smart bomb” treatment, researchers linked trastuzumab to a toxin that kills cells once it gets inside them. This new drug is called T-DM1, the “smart bomb.” Herceptin binds the toxin to the cancer cells, and the toxin provides the coup de gras for the cancer cell. Doctors tested T-DM1 in 991 women who suffered from breast cancer that had spread throughout their body and was getting worse despite treatments with available chemotherapy and ordinary Herceptin. The women in this study were given T-DM1 infusions every three weeks or infusions of standard breast cancer treatment drugs (Xeloda plus daily Tykerb pills). The median time until cancer worsened was nearly 10 months in the women given T-DM1, in comparison to just over 6 months for those who received the other treatments. According to Blackwell, this is about the same magnitude of benefit initially seen with Herceptin, which later proved to improve overall survival
Even more interestingly, T-DM1 caused fewer side effects than the other drugs. Unfortunately, some women on T-DM1 showed had signs of liver damage and poor blood clotting, but most patients did not show the usual problems of chemotherapy. According the Blackwell, “People don’t lose their hair, they don’t throw up. They don’t need nausea medicines, they don’t need transfusions.”

Dr. Michael Link, a pediatric cancer specialist at Stanford University who is president of the American Society of Clinical Oncology, the group hosting the Chicago conference where the results were being presented, said “The data are pretty compelling. It’s sort of a smart bomb kind of therapy, a poison delivered to the tumor … and not a lot of other collateral damage to other organs.”

Dr. Louis Weiner, director of Georgetown Lombardi Comprehensive Cancer Center, said the results strongly suggest T-DM1 improves survival, since it delivers more drug directly to tumors with less side effects. This is a clear advance over other chemotherapeutic drugs.

Denise Davis, 51, a customer service representative at a propane company, was diagnosed three years ago with breast cancer that had spread to her liver and bones. Since February of last year, the Lynchburg, Va., woman has made the two-hour trip to Duke in Durham, N.C., every three weeks to get infusions of T-DM1. Davis called T-DM1 “Herceptin-plus.” Cancer scans every six weeks show her tumors are either shrinking or stable. Davis concluded, “Right now, I’m feeling pretty good about it. The only way I’d feel a little better is if it took care of everything, but I’ll take what I can get.”

Genentech, part of the Swiss company Roche, plans to seek approval later this year to sell the drug in Europe and the United States. Another company, ImmunoGen Inc., made the technology that combined the two drugs. Genentech says the price of T-DM1 has not been determined. Herceptin costs more than $4,000 a month plus whatever doctors charge to infuse it. Herceptin’s U.S. patent will not expire until 2019.