Researchers from the Rappaport Faculty of Medicine at the Technion and from Utrecht University in the Netherlands showed that chemotherapy drugs, beyond their ability to kill tumor cells, are also able to increase the risk of a metastic process in mice. A number of different mechanisms have been suggested in order to explain the metastic process after chemotherapy and it may be that these mechanisms coexist. Dr. Yuval Shaked of the Technion and Prof. Emile Voest of Utrecht University published their findings in the scientific journal, Cancer Research.
Researchers in Dr. Yuval Shaked’s laboratory have been working for several years on trying to understand how cancer cells successfully escape conventional therapy and why they can develop resistance to different types of therapies. In opposition to other studies in the field, which generally concentrate on the ability of cancer cells to develop resistance to therapy, this lab focuses on a different area: the working hypothesis is that in addition to changes initiated in the cancer cells following therapy, other cells in the host – the human body – also change, and are liable, in effect, to contribute to tumor growth, and the development of resistance to treatment. In other words, the tumor “calls” for help following treatment and the host cells respond to this call.
In practice, this group previously showed that the process of new blood vessel creation in cancer – a critical process in tumor development – becomes aggressive specifically after anti-cancer treatment, e.g., after chemotherapy. The creation of new blood vessels during cancer growth is a well-known process but in earlier research by this group, they found that the generation of blood vessels in cancer becomes significant and intensive after different chemotherapy treatments. As a result, this can explain, at least in part, the success of therapies that incapacitate new blood vessels only when combined with different chemotherapy treatments but not when administered alone. This work, which was published a number of years ago in the scientific journal Cancer Cell, motivated Dr. Shaked’s lab to continue investigating the link between anti-cancer treatment and the way cancer cells respond during different stages of therapy – the response requires the assistance of various cells found in the host.
Recently, two papers were published in Cancer Research by two separate teams of researchers – one by the Technion (Dr. Yuval Shaked) and the second by a team from Utrecht University (Prof. Emile Voest). The papers showed that chemotherapy drugs, asides from their ability to kill tumor cells, are also able to increase the risk of metastatic spread in mice. A number of different mechanisms have been suggested for explaining the metastatic spread process following chemotherapy, and it is likely that these mechanisms coexist.
Dr. Svetlana Gingis-Velitski, the leading researcher in the Technion’s team, demonstrated that plasma from mice primed with chemotherapy drugs cause cancer cells to undergo a process similar to that of metastatic cells. She found that one reason for this phenomenon was the activation of different bone marrow cells that colonize the treated tumor and secrete enzymes that break up the extracellular matrix, and thereby contribute to the invasiveness of cancer cells and their movement within the tissue until they reach different areas, in other words, become metastases. When she used materials or drugs that neutralized these enzymes, the chemotherapy treatment did not cause metastasis spread.
These findings suggest that chemotherapy has negative side effects not only in terms of its toxicity but that it is even able to increase the factors contributing to processes in the host that bring about a significant contribution to the tumors, and it is very likely that these phenomena contribute to the decrease in effectiveness of chemotherapy in patients. In different clinical cases it was found that sometimes anti-cancer drug therapy does indeed help in significantly reducing the size of the primary tumor, but for some reason, patients’ survival is not extended despite the use of the effective therapy. Possibly, the secretions of various factors by the host, as described in the above papers, contribute to the metastic process that harms the patient and does not extend their survival.
Dr. Yuval Shaked, the research supervisor and the laboratory head, said that “if we find the factors that are secreted by the host and that contribute to the growth of metastases after chemotherapy, then we will have new tools and new cancer targets that are yet to be identified. Blocking these factors in combination with conventional therapy, i.e., chemotherapy, is liable to significantly increase the success of this treatment.”
Dr. John Ebos of the Department of Medicine at Roosevelt Park Cancer Institute agrees that the findings of the two groups of researchers are very important and that they explain why the efficacy of chemotherapy is limited in certain patients and are, therefore, important in helping to find out how to improve the effectiveness of this treatment.
Prof. Sara Courtneidge of the Medical Research Institute in Stanford-Barnham said: “I hope that these papers encourage additional research that will investigate the mechanisms creating metastatic tumor growth that are the results of chemotherapy and consider integrated treatment in light of these mechanisms, because physicians will not stop using chemotherapy.”
Actually, Dr. Shaked’s laboratory, in combination with a number of hospitals in the country and around the world, primarily Rambam Medical Center in Haifa and the Director of Oncology, Prof. Abraham Kuten, HaEmek Medical Center in Afula (Dr. David Loven), as well as the European Institute of Oncology in Milan, Italy (Prof. Francesco Bertolini) are working together in order to investigate whether these worrisome findings in mice also appear prominently in clinical practice and if so, whether these factors can be used to predict which patients will benefit from what kind of chemotherapy.
Additionally, students, post-doctoral fellows, and employees in Dr. Shaked’s lab – Dr. Ella Fremder, Tali Voloshin, Rotem Bril, Dror Alishekevitz, Michal Munster, Liat Benayoun, and Valeria Miller – are all working hard today on other host components that are likely to be involved in the above mentioned findings. “We are in the midst of a process of establishing a consortium to continue the research on the cancerous effects of chemotherapy drugs and to identify new treatment targets,” says Dr. Shaked. “The consortium at the moment includes academic teams and private companies from Sweden, Greece, France, Germany, Ireland, Italy, and, of course, Israel.”