Abstract
The HuPrime® human gastric neuroendocrine carcinoma derived xenograft model GA0087 was established in this study. GA0087 PDX model showed high gene expression of vascular endothelial growth factors (VEGF)-A and B, and high potential of lung metastasis. Circulating tumor cells (CTCs) with either large or small size, circulating tumor microemboli (CTM) and lung metastatic lesions were detected in GA0087 PDX mice. The number of CTC correlated to the number of metastatic nodules in lung. Both primary tumor growth and metastasis in terms of the number of dynamically monitored CTCs and metastatic nodules were effectively suppressed by Cisplatin. Diverse subtypes of CTCs in the context of sensitivity to Cisplatin were specifically identified by subtraction enrichment (SE) integrated with in situ Phenotyping of cytokeratin 18 (CK18) and Karyotyping of chromosome 8 (in situ PK CTC by CK-iFISH). All the CK18-/diploid and majority of CK18+/diploid CTC subtypes were chemosensitive, whereas a higher percentage of CK18+/multiploid subtype of CTC were Cisplatin-insensitive. Combined histopathological examination of metastatic lesion and in situ PK CTC in a metastatic PDX (mPDX) tumor model are of particular significance, and may provide an unique and robust platform for cancer research as well as pre-clinical evaluation of therapeutic efficacy of new anti-cancer drugs.
Highlights
Gastric cancer (GC) leads to the 3rd cancerrelated mortality worldwide [1]
In contrast to conventional measuring tumor mass and enumerating metastatic nodules alone, comprehensive characterization of metastasis performed by the combined immuno-histopathological examination of metastatic lesion and in situ phenotypic and karyotypic characterization of Circulating tumor cells (CTCs) in a metastatic patient derived xenograft (PDX) tumor model are of particular significance for cancer research as well as development of new anticancer therapeutic strategies and agents
Metastatic lesions in the lung of GA0087 mice were shown in Figure 1A-c, indicating that the established GA0087 was an authentic metastatic PDX model
Summary
Advantages of novel preclinical patient derived xenograft (PDX) models over the traditional tumor animal models established with cancer cell lines for development of anti-cancer drugs have been reported [4,5,6,7]. Unlike cell lines showing great genetic divergence comparing to the primary tumors in cancer patients, PDX models closely recapitulate the heterogeneity of patients’ primary tumors and possess biological stability of gene-expression and mutational status, etc. Such superiorities offer the promise that PDX models will predict new anti-cancer drug efficacy including both sensitivity as well as resistance more reliably than cancer cell lines [7, 8]. PDX model with high metastasizing potential has been reported rarely
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