title: Mathematical modeling of tumor cell proliferation kinetics and label retention in a mouse model of lung cancer.
abstract: Slowly cycling tumor cells that may be present in human tumors may evade cytotoxic therapies, which tend to be more efficient at destroying cells with faster growth rates. However, the proportion and growth rate of slowly cycling tumor cells is often unknown in preclinical model systems used for drug discovery. Here, we report a quantitative approach to quantitate slowly cycling malignant cells in solid tumors, using a well-established mouse model of Kras-induced lung cancer (Kras(G12D/+)). 5-Bromo-2-deoxyuridine (BrdUrd) was administered to tumor-bearing mice, and samples were collected at defined times during pulse and chase phases. Mathematical and statistical modeling of the label-retention data during the chase phase supported the existence of a slowly cycling label-retaining population in this tumor model and permitted the estimation of its proportion and proliferation rate within a tumor. The doubling time of the slowly cycling population was estimated at approximately 5.7 weeks, and this population represented approximately 31% of the total tumor cells in this model system. The mathematical modeling techniques implemented here may be useful in other tumor models where direct observation of cell-cycle kinetics is difficult and may help evaluate tumor cell subpopulations with distinct cell-cycling rates.
authors.affiliation: Cancer Biology Program, Division of Hematology, Oncology, Stem Cell Transplantation and Cancer Biology, Department of Pediatrics, Pharsight Corp., Sunnyvale.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Helen
authors.initials: H
authors.lastname: Moore
authors.forename: Alexandra
authors.initials: A
authors.lastname: Piryatinska
authors.forename: Trinidad
authors.initials: T
authors.lastname: Solis
authors.forename: E Alejandro
authors.initials: EA
authors.lastname: Sweet-Cordero
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000008:administration & dosage / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009930:Organic Chemicals / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014183:Transplantation, Heterologous
chemical_list: C417664:Alexa594; D005456:Fluorescent Dyes; D009930:Organic Chemicals; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D001973:Bromodeoxyuridine