Increasing aggressiveness of patient-derived xenograft models of cervix carcinoma during serial transplantation.

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.