Long-term progression and therapeutic response of visceral metastatic disease non-invasively monitored in mouse urine using β-human choriogonadotropin secreting tumor cell lines

Abstract

Historically, the use of mouse models of metastatic disease to evaluate anticancer therapies has been hampered because of difficulties in detection and quantification of such lesions without sacrificing the mice, which in turn may also be dictated by institutional or ethical guidelines. Advancements in imaging technologies have begun to change this situation. A new method to noninvasively measure tumor burden, as yet untested to monitor spontaneous metastases, is the use of transplanted tumors expressing secretable human B-chorionic gonadotropin (B-hCG) that can be measured in urine. We describe examples of B-hCG -transfected tumor cell lines for evaluating the effect of different therapies on metastatic disease, which in some cases involved monitoring tumor growth for >100 days. We used B-hCG -tagged mouse B16 melanoma and erbB-2/Her-2 -expressing human breast cancer MDA-MB-231 models, and drug treatments included metronomic low-dose cyclophosphamide chemotherapy with or without a vascular endothelial growth factor receptor 2 -targeting antibody (DC101) or trastuzumab, the erbB-2/Her-2 -targeting antibody. Both experimental and spontaneous metastasis models were studied; in the latter case, an increase in urine B-hCG always foreshadowed the development of lung, liver, brain, and kidney metastases. Metastatic disease was unresponsive to DC101 or trastuzumab monotherapy treatment, as assessed by B-hCG levels. Our results also suggest that B-hCG levels may be set as an end point for metastasis studies, circumventing guidelines, which have often hampered the use of advanced disease models. Collectively, our data indicates that B-hCG is an effective noninvasive preclinical marker for the long term monitoring of untreated or treated metastatic disease. [Mol Cancer Ther 2008;7(10):3452 -9]

Issues regarding improving the impact of antiangiogenic drugs for the treatment of breast cancer

“…This leads to the concept of low-dose ‘metronomic’ chemotherapy, a therapeutic strategy which we have been studying actively for almost a decade, including in the context of MBC. 27,45–48 …”

Mouse models of advanced spontaneous metastasis for experimental therapeutics

“…An example of this kind of discrepancy was observed when we compared the response of primary tumours with macroscopic metastases to various antibody-based drugs. Thus, using the metastatic ERBB2-positive breast cancer cell line 36,46 (H2N/met2) we noted that treatment with the monoclonal antibody trastuzumab alone did not affect the growth of established visceral metastases, whereas it potently inhibited the corresponding cells that were grown as established orthotopic primary tumours. A similar observation was noted when the parental MDA-MB-231 breast cancer was implanted orthotopically; this resulted in the development of both primary tumours and distant metastases 48 .…”

“…One such variant, called 231/LM2-4, aggressively and spontaneously metastasizes to various host organs such as the liver and lungs 34 . Additionally, we developed the first ERBB2-positive breast cancer model of advanced visceral spontaneous metastasis 36,46 . MDA-MB-231 triple-negative cells (that is, breast cancer cells that do not express oestrogen receptor (ER), progesterone receptor (PR) or ERBB2) were first genetically manipulated to express high levels of ERBB2 by gene transduction 47 , and the resulting cell line, H2N/met2, was used to select sublines that had competence for spontaneous metastatic spread by the aforementioned strategy 36,46 (FIG.…”

A Novel Model of Metastatic Conjunctival Melanoma in Immune-Competent Mice

“…As noted above, an advantage of our allogeneic model reported here is that the tumor develops in healthy, immunecompetent animals, and does not require genetic modifications or inactivation of the immune system, in contrast to the xenograft approaches, in which human tumor cells are orthotopically transplanted in SCID mice [34][35][36] or athymic nude mice. [37][38][39][40] It is well accepted that the tumor microenvironment is essential for progression of tumors, 41,42 therefore our model presented here allows studying the effect of the tumor microenvironment on the host's immune system, neovascularization, and metastasis.…”