![]() The majority of tumor grafts were in addition metastatic and produced patterns of metastasis similar to those of the patients from which the tumor samples were originally taken. Importantly ER+ tumor grafts retained estrogen dependence for tumor growth, mirroring a key physiological characteristic of ER+ breast tumors in humans. Staining and antibody assays indicated that human stroma was largely lost after engraftment and was replaced by mouse stroma including mouse leukocyte, fibrobalsts, and endothelial cells. Importantly, evaluation of stained tumors demonstrated that all the grafts retained the major characteristics of the original tumors, even after multiple passages in mice. Interestingly, triple-negative breast cancers tumors (i.e., those that were ER negative (ER−), progesterone receptor negative (PR−), and HER2 negative (HER2−)), usually grew the fastest, which is a phenomenon often observed in the clinic, the team notes. Analyses suggested the likelihood of success wasn’t related to the amount of tumor transplanted or the tumor-to-stromal tissue ratio in the samples. Tumors grew from 18 out of 49 samples (37%), and the researchers successfully maintained 12 tumor lines from 10 subjects through multiple rounds of serial transplantation. Four of the grafts were from primary tumors, and eight were from metastatic effusions. Five tumor grafts were estrogen receptor and progesterone receptor positive (ER+PR+), seven were ER and PR negative (ER−PR−), and five were positive for HER2 (HER2+). The tissue was obtained immediately following surgery or fluid drainage from 42 different individuals. To this end they transplanted 49 fresh primary tumors or metastatic breast cancer cell samples into cleared mammary fat pads of female nonobese diabetic severe combined immunodeficiency (NOD-SCID) mice. The team’s aim was thus to generate an animal model of breast cancer in which tumor tissue taken directly from a patient would retain the critical characteristics of the original tumor specimen, including metastasis. “Although the majority (about 70%) of newly diagnosed breast cancers are positive for ER, this tumor type is underrepresented in mouse models because of loss of ER expression or lack of estrogen dependence.” Moreover, they note, there is a similar lack of models that show spontaneously, clinically relevant metastasis, which is the primary cause of death from breast cancer. Transplantation of tumor tissue into immune-deficient mice is more informative in terms of predicting drug responses, but, as the Huntsman team points out, tumor graft strategies for hormone-driven cancers such as breast or prostate cancer have had limited success. Implanted breast cancer cell lines have been informative, but only partly recapitulate the genetic features and metastatic potential of tumors in individuals with breast cancer, and this doesn’t help scientists predict how drugs will perform in a clinical setting. The development of new treatments for breast cancer has been hampered by the lack of in vivo models in which the human tumor continues to behave exactly as it would in a human patient, the researchers note. They report their work in a paper titled “Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes.” Welm, M.D., and colleagues, claim their approach could pave the way to the development of models that will help predict the progression and outcome of breast cnacer in individual patients. The results, published in Nature Medicine, also showed that the ability of a tumor from an individual with breast cancer to grow as a graft is a key indicator of shorter survival time, even for patients with no sign of metastases. ![]()
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