Long-term progression and therapeutic response of visceral metastatic disease non-invasively monitored in mouse urine using beta-human choriogonadotropin secreting tumor cell lines.
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 non-invasively measure tumor burden, as yet untested to monitor spontaneous metastases, is the use of transplanted tumors expressing secretable human beta-chorionic gonadotropin (beta-hCG) that can be measured in urine. We describe examples of beta-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 beta-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 beta-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 beta-hCG levels. Our results also suggest that beta-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 beta-hCG is an effective noninvasive preclinical marker for the long term monitoring of untreated or treated metastatic disease.
Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, S-217, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
Giulio
G
Francia
Urban
U
Emmenegger
Christina R
CR
Lee
Yuval
Y
Shaked
Christopher
C
Folkins
Miriam
M
Mossoba
Jeffrey A
JA
Medin
Shan
S
Man
Zhenping
Z
Zhu
Larry
L
Witte
Robert S
RS
Kerbel
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000378:metabolism / Q000652:urine*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000473:pathology* / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013997:Time Factors; D014781:Viscera / Q000187:drug effects / Q000473:pathology*
D020533:Angiogenesis Inhibitors; D018997:Chorionic Gonadotropin, beta Subunit, Human; D003520:Cyclophosphamide; D018719:Erb-b2 Receptor Tyrosine Kinases