Patient-derived Xenografts from Colorectal Carcinoma: A Temporal and Hierarchical Study of Murine Stromal Cell Replacement

Chao, Celia; Widen, Steve G.; Wood, Thomas G.; Zatarain, John R.; Johnson, Paul; Gajjar, Aakash; Gómez, Guillermo A.; Qiu, Suimin; Thompson, Jill C.; Spratt, Heidi; Hellmich, Mark R.

doi:10.21873/anticanres.11707

Cited by 21 publications

(18 citation statements)

References 25 publications

(36 reference statements)

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“…However, the organization of epithelial and stromal cells relative to each other was recapitulated in the PDX tumors. This is consistent with previous reports that the epithelial cells that are of human origin can instruct the murine stromal cells to organize spatially in order to support human cancer cell growth [52].…”

Section: The Patient-derived Xenografts Maintained the Histological Fsupporting

confidence: 93%

“…However, other studies suggest that when human CRC tumor cell suspensions were injected subcutaneously, instead of tumor fragments, that the human stromal cells were still present in P1 [80] and P2 [82]. However, murine stromal cells have been reported as early as P0, the initial transplant, with the increase in murine stroma proportional to the tumor mass [52]. The interaction of human tumor cells with the surrounding stromal cells is important for the retention of the tissue architecture of the parental tumor after implantation [83], and may impact treatment response if murine signals can feedback onto tumor cells.…”

Section: Discussionmentioning

confidence: 99%

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A Biobank of Colorectal Cancer Patient-Derived Xenografts

Abdirahman

Christie

Preaudet

et al. 2020

Cancers

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Colorectal cancer (CRC) is a challenging disease, with a high mortality rate and limited effective treatment options, particularly for late-stage disease. Patient-derived xenografts (PDXs) have emerged as an informative, renewable experimental resource to model CRC architecture and biology. Here, we describe the generation of a biobank of CRC PDXs from stage I to stage IV patients. We demonstrate that PDXs within our biobank recapitulate the histopathological and mutation features of the original patient tumor. In addition, we demonstrate the utility of this resource in pre-clinical chemotherapy and targeted treatment studies, highlighting the translational potential of PDX models in the identification of new therapies that will improve the overall survival of CRC patients.

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Section: The Patient-derived Xenografts Maintained the Histological Fsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

A Biobank of Colorectal Cancer Patient-Derived Xenografts

Abdirahman

Christie

Preaudet

et al. 2020

Cancers

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“…Human stromal cells are not well sustained when inoculated in mice; instead, they are replaced by stromal cells of mouse origin, e.g. , patient-derived xenograft tumors showed replacement of 75% human stromal cells after 4 weeks of inoculation [46] , [47] . Activated HSCs play critical roles in EMT induction by secreting various growth factors in HCC [15] , [48] .…”

Section: Discussionmentioning

confidence: 99%

Three Dimensional Mixed-Cell Spheroids Mimic Stroma-Mediated Chemoresistance and Invasive Migration in hepatocellular carcinoma

et al. 2018

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Interactions between cancer cells and cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) play an important role in promoting the profibrotic microenvironment and epithelial-mesenchymal transition (EMT), resulting in tumor progression and drug resistance in hepatocellular carcinoma (HCC). In the present study, we developed a mixed-cell spheroid model using Huh-7 HCC cells and LX-2 stellate cells to simulate the in vivo tumor environment with respect to tumor-CAF interactions. Spheroids were cultured from cancer cells alone (monospheroids) or as a mixture (mixed-cell spheroids) in ultra-low-attachment plates. Compact, well-mixed, and stroma-rich mixed-cell spheroids were successfully established with heterotypic cell-cell contacts shown by the presence of gap junctions and desmosomes. Mixed-cell spheroids showed enhanced expression of collagen type-I (Col‐I) and pro‐fibrotic factors such as, transforming growth factor beta1 (TGF-β1), and connective tissue growth factor (CTGF) compared to the levels expressed in mono-spheroids. The EMT phenotype was evident in mixed-cell spheroids as shown by the altered expression of E-cadherin and vimentin. Differential drug sensitivity was observed in mixed-cell spheroids, and only sorafenib and oxaliplatin showed dose-dependent antiproliferative effects. Simultaneous treatment with TGF-β inhibitors further improved sorafenib efficacy in the mixed-cell spheroids, indicating the involvement of TGF-β in the mechanism of sorafenib resistance. In 3D matrix invasion assay, mixed-cell spheroids exhibited fibroblast-led collective cell movement. Overall, our results provide evidence that mixed-cell spheroids formed with Huh-7 and LX-2 cells well represent HCC tumors and their TME in vivo and hence are useful in studying tumor-stroma interactions as mechanisms associated with drug resistance and increased cell motility.

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“…Interestingly, human tumor EC-like cells showed lower QE and number of mixture components when compared to mouse tumor EC-like cells (Figure 2G ). We suspect that the likely loss of human tumor-associated cells over time in a PDX model (Chao et al, 2017 ) may be the reason why human tumor EC-like cells present a more homogenous state than the mouse tumor EC-like cells.…”

Section: A New Approach For Examining Gbm Heterogeneitymentioning

confidence: 99%

Characterizing Glioblastoma Heterogeneity via Single-Cell Receptor Quantification

Chen

Harley

et al. 2018

Front. Bioeng. Biotechnol.

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Dysregulation of tyrosine kinase receptor (RTK) signaling pathways play important roles in glioblastoma (GBM). However, therapies targeting these signaling pathways have not been successful, partially because of drug resistance. Increasing evidence suggests that tumor heterogeneity, more specifically, GBM-associated stem and endothelial cell heterogeneity, may contribute to drug resistance. In this perspective article, we introduce a high-throughput, quantitative approach to profile plasma membrane RTKs on single cells. First, we review the roles of RTKs in cancer. Then, we discuss the sources of cell heterogeneity in GBM, providing context to the key cells directing resistance to drugs. Finally, we present our provisionally patented qFlow cytometry approach, and report results of a “proof of concept” patient-derived xenograft GBM study.

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Patient-derived Xenografts from Colorectal Carcinoma: A Temporal and Hierarchical Study of Murine Stromal Cell Replacement

Cited by 21 publications

References 25 publications

A Biobank of Colorectal Cancer Patient-Derived Xenografts

A Biobank of Colorectal Cancer Patient-Derived Xenografts

Three Dimensional Mixed-Cell Spheroids Mimic Stroma-Mediated Chemoresistance and Invasive Migration in hepatocellular carcinoma

Characterizing Glioblastoma Heterogeneity via Single-Cell Receptor Quantification

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