Tumor Take Rate Optimization for Colorectal Carcinoma Patient-Derived Xenograft Models

Gock, Michael; Kühn, Florian; Mullins, Christina Susanne; Krohn, Mathias; Prall, Friedrich; Klar, E.; Linnebacher, Michael

doi:10.1155/2016/1715053

Cited by 27 publications

(16 citation statements)

References 21 publications

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“…We here addressed the question to which extent mERV are activated and possibly transmitted to human CRC cells when passaged as PDX in immunodeficient mice. Technically, this approach was possible due to a large collection of low-passage, patient-derived tumor models including PDX and matching tumor- and PDX-derived permanent cell lines ( Maletzki et al, 2015 ; Gock et al, 2016 ; Kuehn et al, 2016 ; Mullins et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Murine Endogenous Retroviruses Are Detectable in Patient-Derived Xenografts but Not in Patient-Individual Cell Lines of Human Colorectal Cancer

et al. 2018

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Endogenous retroviruses are remnants of retroviral infections. In contrast to their human counterparts, murine endogenous retroviruses (mERV) still can synthesize infectious particles and retrotranspose. Xenotransplanted human cells have occasionally been described to be mERV infected. With genetic engineered mice and patient-derived xenografts (PDXs) on the rise as eminent research tools, we here systematically investigated, if different tumor models harbor mERV infections. Relevant mERV candidates were first preselected by next generation sequencing (NGS) analysis of spontaneous lymphomas triggered by colorectal cancer (CRC) PDX tissue. Two primer systems were designed for each of these candidates (AblMLV, EcoMLV, EndoPP, MLV, and preXMRV) and implemented in an quantitative real-time (RT-qPCR) screen using murine tissues (n = 11), PDX-tissues (n = 22), PDX-derived cell lines (n = 13), and patient-derived tumor cell lines (n = 14). The expression levels of mERV varied largely both in the PDX samples and in the mouse tissues. No mERV signal was, however, obtained from cDNA or genomic DNA of CRC cell lines. Expression of EcoMLV was higher in PDX than in murine tissues; for EndoPP it was the opposite. These two were thus further investigated in 40 additional PDX. In addition, four patient-derived cell lines free of any mERV expression were subcutaneously injected into immunodeficient mice. Outgrowing cell-derived xenografts barely expressed EndoPP. In contrast, the expression of EcoMLV was even higher than in surrounding mouse tissues. This expression gradually vanished within few passages of re-cultivated cells. In summary, these results strongly imply that: (i) PDX and murine tissues in general are likely to be contaminated by mERV, (ii) mERV are expressed transiently and at low level in fresh PDX-derived cell cultures, and (iii) mERV integration into the genome of human cells is unlikely or at least a very rare event. Thus, mERVs are stowaways present in murine cells, in PDX tissues and early thereof-derived cell cultures. We conclude that further analysis is needed concerning their impact on results obtained from studies performed with PDX but also with murine tumor models.

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Section: Discussionmentioning

confidence: 99%

Murine Endogenous Retroviruses Are Detectable in Patient-Derived Xenografts but Not in Patient-Individual Cell Lines of Human Colorectal Cancer

et al. 2018

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“…A previous study in nude mice looked at optimization of “take rates” using cryogenically frozen colorectal carcinomas with the aid of Matrigel ® . In their study, Matrigel ® significantly improved their overall take rate to 70% ( Gock et al, 2016 ). In another study using nude mice, xenografts successfully established 62.2% of the time.…”

Section: Discussionmentioning

confidence: 94%

Assessment of a mouse xenograft model of primary colorectal cancer with special reference to perfluorooctane sulfonate

Wimsatt

Montgomery

Thomas

et al. 2018

PeerJ

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Colorectal cancer ranks third among the most commonly diagnosed cancers in the United States. Current therapies have a range of side effects, and the development of a reliable animal model to speed the discovery of safe effective preventative therapies would be of great value. A cross-sectional study in a large Appalachian population recently showed an association between low circulating levels of perfluorooctane sulfonate (PFOS) and a reduced prevalence of colorectal cancer. A study using APCmin (C57BL/6J-ApcMin/J) mice prone to familial adenomatous polyposis found PFOS was protective when exposure occurred during tumor development. To test the possible benefit of PFOS on spontaneous colorectal cancer, we developed a mouse model utilizing primary patient colorectal cancer implants into NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl/Sz) mice. Study goals included: (1) to assess potential factors supporting the successful use of colorectal cancer from heterogeneous tumors for PDX studies; and, (2) evaluate PFOS as a therapy in tumor matched pairs of mice randomized to receive PFOS or vehicle. The time in days for mice to grow primary tumors to 5 mm took almost 2 months (mean = 53.3, se = 5.7, range = 17–136). Age of mice at implantation, patient age, gender and race appeared to have no discernable effect on engraftment rates. Engraftment rates for low and high-grade patient tumors were similar. PFOS appeared to reduce tumor size dramatically in one group of tumors, those from the right ascending colon. That is, by 5 weeks of treatment in two mice, PFOS had eliminated their 52.4 mm3 and 124.6 mm3 masses completely, an effect that was sustained for 10 weeks of treatment; in contrast, their corresponding matched vehicle control mice had tumors that grew to 472.7 mm3 and 340.1 mm3 in size respectively during the same period. In a third xenograft mouse, the tumor growth was dramatically blunted although not eliminated, and compared favorably to their matched vehicle controls over the same period. These preliminary findings suggested that this mouse model may be advantageous for testing compounds of potential value in the treatment of colorectal cancer, and PFOS may have utility in selected cases.

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“…In vitro and in vivo approaches were combined as described previously for establishment of a permanent cell line growing 2D[ 19 ] and a subcutaneous PDX[ 27 ]. Outgrowth of cells in culture occurred immediately and doubling time of the outgrowing cell line was 26.13 h.…”

Section: Resultsmentioning

confidence: 99%

Establishment, functional and genetic characterization of a colon derived large cell neuroendocrine carcinoma cell line

Gock

Mullins

Harnack

et al. 2018

WJG

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AIMTo establish cell line and patient-derived xenograft (PDX) models for neuroendocrine carcinomas (NEC) which is highly desirable for gaining insight into tumor development as well as preclinical research including biomarker testing and drug response prediction.METHODSCell line establishment was conducted from direct in vitro culturing of colonic NEC tissue (HROC57). A PDX could also successfully be established from vitally frozen tumor samples. Morphological features, invasive and migratory behavior of the HROC57 cells as well as expression of neuroendocrine markers were vastly analyzed. Phenotypic analysis was done by microscopy and multicolor flow cytometry. The extensive molecular-pathological profiling included mutation analysis, assessment of chromosomal and microsatellite instability; and in addition, fingerprinting (i.e., STR analysis) was performed from the cell line in direct comparison to primary patient-derived tissues and the PDX model established. Drug responsiveness was examined for a panel of chemotherapeutics in clinical use for the treatment of solid cancers.RESULTSThe established cell line HROC57 showed distinct morphological and molecular features of a poorly differentiated large-cell NEC with KI-67 > 50%. Molecular-pathological analysis revealed a CpG island promoter methylation positive cell line with microsatellite instability being absent. The following mutation profile was observed: KRAS (wt), BRAF (mut). A high sensitivity to etoposide, cisplatin and 5-FU could be demonstrated while it was more resistant towards rapamycin.CONCLUSIONWe successfully established and characterized a novel patient-derived NEC cell line in parallel to a PDX model as a useful tool for further analysis of the biological characteristics and for development of novel diagnostic and therapeutic options for NEC.

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Tumor Take Rate Optimization for Colorectal Carcinoma Patient-Derived Xenograft Models

Cited by 27 publications

References 21 publications

Murine Endogenous Retroviruses Are Detectable in Patient-Derived Xenografts but Not in Patient-Individual Cell Lines of Human Colorectal Cancer

Murine Endogenous Retroviruses Are Detectable in Patient-Derived Xenografts but Not in Patient-Individual Cell Lines of Human Colorectal Cancer

Assessment of a mouse xenograft model of primary colorectal cancer with special reference to perfluorooctane sulfonate

Establishment, functional and genetic characterization of a colon derived large cell neuroendocrine carcinoma cell line

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