Abstract
In this study, we established patient-derived tumor cell (PDC) models using tissues collected from patients with metastatic cancer and assessed whether these models could be used as a tool for genome-based cancer treatment. PDCs were isolated and cultured from malignant effusions including ascites and pleural fluid. Pathological examination, immunohistochemical analysis, and genomic profiling were performed to compare the histological and genomic features of primary tumors, PDCs. An exploratory gene expression profiling assay was performed to further characterize PDCs. From January 2012 to May 2013, 176 samples from patients with metastatic cancer were collected. PDC models were successfully established in 130 (73.6%) samples. The median time from specimen collection to passage 1 (P1) was 3 weeks (range, 0.5-4 weeks), while that from P1 to P2 was 2.5 weeks (range, 0.5-5 weeks). Sixteen paired samples of genomic alterations were highly concordant between each primary tumor and progeny PDCs, with an average variant allele frequency (VAF) correlation of 0.878. We compared genomic profiles of the primary tumor (P0), P1 cells, P2 cells, and patient-derived xenografts (PDXs) derived from P2 cells and found that three samples (P0, P1, and P2 cells) were highly correlated (0.99-1.00). Moreover, PDXs showed more than 100 variants, with correlations of only 0.6-0.8 for the other samples. Drug responses of PDCs were reflective of the clinical response to targeted agents in selected patient PDC lines. Our results provided evidence that our PDC model was a promising model for preclinical experiments and closely resembled the patient tumor genome and clinical response.
Highlights
With rapid advances in molecular oncology, the availability of preclinical in vitro cell models and in vivo animal models with specific genomic aberrations is critical for improved prediction of clinical outcomes in cancer patients
One of the most widely used preclinical models is conventional cell lines, such as the NCI-60 panel of cell lines [1]; these cell lines are widely used in preclinical testing for novel targeted drugs, partially owing to the low expense and reduced labor associated with cell culture compared with other preclinical models, such as animal xenografts
Successful patient-derived tumor cell (PDC) were defined as those cells that were cytologically confirmed by a designated pathologist (M.H. or I.D.) and those that maintained growth following two passages
Summary
With rapid advances in molecular oncology, the availability of preclinical in vitro cell models and in vivo animal models with specific genomic aberrations is critical for improved prediction of clinical outcomes in cancer patients. Recent studies have shown that accumulation of genetic aberrations in cancer cell lines occurs with increasing passage number These models lack the heterogeneity of tumors and do not exhibit a proper microenvironment, highlighting the limitations of cell-based models [2,3,4,5]. PDX is generated by directly transplanting freshly resected patient tumors into immunocompromised murine hosts with or without an intermediate in vitro culture step [10]. This PDX model is an improvement over cell lines because it can provide both an appropriate tumor microenvironment and heterogeneity of tumor cells. We established patient-derived tumor cell (PDC) models using tissues collected from patients with metastatic cancer and assessed whether these models could be used as a tool for genome-based cancer treatment
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