CAMBRIDGE, Mass.—Over the last 40 years, chemotherapy has helped millions of cancer patients overcome their disease, but most chemotherapeutic regimens still fail to cure many cancer patients because a small number of cancer cells escape chemotherapy and "hide out" in the thymus. Those cells, according to a new study by biologists at the Massachusetts Institute of Technology (MIT), are likely the source of relapsed tumors.
Publishing their observations in the Oct. 29 issue of the journal Cell, the MIT team says that once cancer cells escape to the thymus, they are "bathed" in pro-survival growth factors that allow them to evade the effects of chemotherapeutic drugs. These findings, says Michael Hemann, an MIT assistant professor of biology and lead author of the study, suggest that a more successful cancer therapy would involve both a component that kills tumor cells as well as one that blocks these pro-survival signals.
"Current cancer therapies fail to target this survival response," Hemann, who is a member of MIT's David H. Koch Institute for Integrative Cancer Research, says. "It has been noted for a variety of cancers that patients can be in remission for sustained periods of time, so presumably, they have a tumor mass present that has not been eradicated by chemotherapeutic treatment. Until now, we did not have a sense of where those tumor burdens lay and how they escape therapy. The first question we wanted to look at was if we could identify where these small sets of tumor cells were hiding."
The MIT biologists set out to investigate the dynamics of lymphoma response and relapse following chemotherapy using a well-established preclinical model of human Burkitt's lymphoma. At tumor onset all mice displayed a characteristic disseminated pattern of disease with lymphoma cells in the peripheral lymph nodes, spleen and mediastinum. Mice were treated with the maximum tolerated dose of the front-line chemotherapeutic doxorubicin at the time of lymphoma manifestation. Three days after administration of doxorubicin, all mice displayed tumor regression and peripheral tumor clearance, measured by lymph node palpation.
The mice were sacrificed at four days post-treatment and sites of minimal residual disease were identified by GFP imaging. The researchers observed that the majority of surviving lymphoma cells were in the mediastinal cavity, a central component of the thoracic cavity that encapsulates the heart, esophagus, trachea and a large amount of lymphatic tissue including the mediastinal lymph nodes and the thymus.
The researchers then analyzed the effect of drug treatment on specific tumor niches by harvesting all primary lymphoid organs, including peripheral lymph nodes, thymus, spleen and bone marrow, following doxorubicin treatment. All tissues sampled showed extensive lymphoma cell apoptosis and restoration of normal organ architecture. Peripheral lymph nodes, spleen and bone marrow exhibited nearly complete tumor clearance with rare surviving lymphoma cells. In contrast, many surviving B lymphoma cells could be seen in the thymus. To quantify this phenotype, cells were harvested from peripheral lymph nodes and the thymus following treatment, and the number of surviving GFP positive lymphoma cells was assessed by flow cytometry. According to the researchers, the number of viable lymphoma cells in the thymus relative to the lymph nodes increased 6.5-fold following doxorubicin treatment. Thus, the thymus represents a chemoprotective niche that protects lymphoma cells from doxorubicin-induced cell death, the researchers concluded.
The researchers also observed that IL-6 and Timp-1 were released in the thymus in response to DNA damage, creating a "chemo-resistant niche" that promotes the survival of a minimal residual tumor burden and serves as a reservoir for eventual tumor relapse. In addition, the researchers further observed that IL-6 is released acutely from thymic endothelial cells in a p38-dependent manner following genotoxic stress, and this acute secretory response precedes the gradual induction of senescence in tumor-associated stromal cells.
Thus, Hemann says, conventional chemotherapies can induce tumor regression, while simultaneously eliciting stress responses that protect subsets of tumor cells in select anatomical locations from drug action. The MIT team's results suggest that chemotherapeutic regimens could be improved if they combined cytotoxic agents, which target tumor cells, and targeted therapeutics that inhibit pro-survival signaling from the tumor-adjacent cells, Hemann adds.
"Traditionally, if you look at what is out there in terms of combination therapies, there is not always a great rationale for why drugs are combined," he says. "I think we are getting to a point where we can start to rationally use chemotherapeutics with drugs that act well in combination with, or offset, the pro-survival response, in a manner that has the greatest efficacy for the patient."
Next, the researchers will use mouse models to test drugs that interfere with one of those protective factors. Those drugs were originally developed to treat arthritis, and are now in clinical trials for that use. Hemann says MIT will also investigate whether this kind of pro-survival signal is elicited in other types of cancer, including tumors that have metastasized.
Hemann's co-author on the study, "DNA Damage-Mediated Induction of a Chemoresistant Niche," was Luke Gilbert, a graduate student in Hemann's lab. The National Institutes of Health, the Ludwig Cancer Center for Molecular Oncology at MIT and an MIT Herman Eisen fellowship provided funding for the study.
Publishing their observations in the Oct. 29 issue of the journal Cell, the MIT team says that once cancer cells escape to the thymus, they are "bathed" in pro-survival growth factors that allow them to evade the effects of chemotherapeutic drugs. These findings, says Michael Hemann, an MIT assistant professor of biology and lead author of the study, suggest that a more successful cancer therapy would involve both a component that kills tumor cells as well as one that blocks these pro-survival signals.
"Current cancer therapies fail to target this survival response," Hemann, who is a member of MIT's David H. Koch Institute for Integrative Cancer Research, says. "It has been noted for a variety of cancers that patients can be in remission for sustained periods of time, so presumably, they have a tumor mass present that has not been eradicated by chemotherapeutic treatment. Until now, we did not have a sense of where those tumor burdens lay and how they escape therapy. The first question we wanted to look at was if we could identify where these small sets of tumor cells were hiding."
The MIT biologists set out to investigate the dynamics of lymphoma response and relapse following chemotherapy using a well-established preclinical model of human Burkitt's lymphoma. At tumor onset all mice displayed a characteristic disseminated pattern of disease with lymphoma cells in the peripheral lymph nodes, spleen and mediastinum. Mice were treated with the maximum tolerated dose of the front-line chemotherapeutic doxorubicin at the time of lymphoma manifestation. Three days after administration of doxorubicin, all mice displayed tumor regression and peripheral tumor clearance, measured by lymph node palpation.
The mice were sacrificed at four days post-treatment and sites of minimal residual disease were identified by GFP imaging. The researchers observed that the majority of surviving lymphoma cells were in the mediastinal cavity, a central component of the thoracic cavity that encapsulates the heart, esophagus, trachea and a large amount of lymphatic tissue including the mediastinal lymph nodes and the thymus.
The researchers then analyzed the effect of drug treatment on specific tumor niches by harvesting all primary lymphoid organs, including peripheral lymph nodes, thymus, spleen and bone marrow, following doxorubicin treatment. All tissues sampled showed extensive lymphoma cell apoptosis and restoration of normal organ architecture. Peripheral lymph nodes, spleen and bone marrow exhibited nearly complete tumor clearance with rare surviving lymphoma cells. In contrast, many surviving B lymphoma cells could be seen in the thymus. To quantify this phenotype, cells were harvested from peripheral lymph nodes and the thymus following treatment, and the number of surviving GFP positive lymphoma cells was assessed by flow cytometry. According to the researchers, the number of viable lymphoma cells in the thymus relative to the lymph nodes increased 6.5-fold following doxorubicin treatment. Thus, the thymus represents a chemoprotective niche that protects lymphoma cells from doxorubicin-induced cell death, the researchers concluded.
The researchers also observed that IL-6 and Timp-1 were released in the thymus in response to DNA damage, creating a "chemo-resistant niche" that promotes the survival of a minimal residual tumor burden and serves as a reservoir for eventual tumor relapse. In addition, the researchers further observed that IL-6 is released acutely from thymic endothelial cells in a p38-dependent manner following genotoxic stress, and this acute secretory response precedes the gradual induction of senescence in tumor-associated stromal cells.
Thus, Hemann says, conventional chemotherapies can induce tumor regression, while simultaneously eliciting stress responses that protect subsets of tumor cells in select anatomical locations from drug action. The MIT team's results suggest that chemotherapeutic regimens could be improved if they combined cytotoxic agents, which target tumor cells, and targeted therapeutics that inhibit pro-survival signaling from the tumor-adjacent cells, Hemann adds.
"Traditionally, if you look at what is out there in terms of combination therapies, there is not always a great rationale for why drugs are combined," he says. "I think we are getting to a point where we can start to rationally use chemotherapeutics with drugs that act well in combination with, or offset, the pro-survival response, in a manner that has the greatest efficacy for the patient."
Next, the researchers will use mouse models to test drugs that interfere with one of those protective factors. Those drugs were originally developed to treat arthritis, and are now in clinical trials for that use. Hemann says MIT will also investigate whether this kind of pro-survival signal is elicited in other types of cancer, including tumors that have metastasized.
Hemann's co-author on the study, "DNA Damage-Mediated Induction of a Chemoresistant Niche," was Luke Gilbert, a graduate student in Hemann's lab. The National Institutes of Health, the Ludwig Cancer Center for Molecular Oncology at MIT and an MIT Herman Eisen fellowship provided funding for the study.
