Abstract
Four patient-derived xenograft (PDX) models (BK-12, ED-15, HL-16, LA-19) of carcinoma of the uterine cervix have been developed in our laboratory, and their stability during serial transplantation in vivo was investigated in this study. Two frozen cell stocks were established, one from xenografted tumors in passage 2 (early generation) and the other from xenografted tumors transplanted serially in mice for approximately two years (late generation), and the biology of late generation tumors was compared with that of early generation tumors. Late generation tumors showed higher incidence of lymph node metastases than early generation tumors in three models (ED-15, HL-16, LA-19), and the increased metastatic propensity was associated with increased tumor growth rate, increased microvascular density, and increased expression of angiogenesis-related and cancer stem cell-related genes. Furthermore, late generation tumors showed decreased fraction of pimonidazole-positive tissue (i.e., decreased fraction of hypoxic tissue) in two models (HL-16, LA-19) and decreased fraction of collagen-I-positive tissue (i.e., less extensive extracellular matrix) in two models (ED-15, HL-16). This study showed that serially transplanted PDXs may not necessarily mirror the donor patients’ diseases, and consequently, proper use of serially transplanted PDX models in translational cancer research requires careful molecular monitoring of the models.
Highlights
Preclinical xenograft models of human cancer reflecting the biology of the donor patients’ tumors are essential tools for conducting clinically relevant cancer research
Four patient-derived xenograft (PDX) models (BK-12, ED-15, HL-16, LA-19) of carcinoma of the uterine cervix have been developed in our laboratory, and their stability during serial transplantation in vivo was investigated in this study
To investigate whether late generation tumors differed from early generation tumors in histological appearance, histological preparations were stained with hematoxylin and eosin (HE) or immunostained for blood vessels, hypoxic tissue, or collagen-I
Summary
Preclinical xenograft models of human cancer reflecting the biology of the donor patients’ tumors are essential tools for conducting clinically relevant cancer research. It has been revealed that cell line-derived xenograft (CDX) models do not mirror accurately the biology of human tumors, and the response to treatment of CDX models may fail to predict the treatment response in cancer patients [1, 2]. The limited clinical relevance of CDX models has initiated an increased interest in establishing improved cancer models by transplanting surgical specimens from human tumors directly into immune-deficient mice [3, 4]. These models are referred to as patient-derived xenograft (PDX) models and are maintained in vivo without being exposed to cell culture conditions in vitro. It has been suggested that PDXs may be useful cancer models in many disciplines of oncologic research, including identification of novel biomarkers, evaluation of potentially useful anticancer agents, and the development of strategies for precision cancer medicine [1, 3, 4, 7, 8]
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