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Establishment and characterization of HROC69 - a Crohn´s related colonic carcinoma cell line and its matched patient-derived xenograft.

Kuehn F, Mullins CS, Krohn M, Harnack C, Ramer R, Krämer OH, Klar E, Huehns M, Linnebacher M - Sci Rep (2016)

Bottom Line: They show strong invasive but in comparison weak migratory activity.The present work is the first description of patient-derived in vitro and in vivo models for CAC from a Crohn´s disease patient.They might be valuable tools for analysis of genetic and epigenetic alterations, biomarker identification, functional testing, including response prediction, and the development of specific therapeutical strategies.

View Article: PubMed Central - PubMed

Affiliation: University Medicine Rostock, Department of General-, Thoracic-, Vascular- and Transplantation Surgery, Rostock, Germany.

ABSTRACT
Colitis-associated colorectal cancer (CAC) seems to be a rather unique entity and differs in its genetic alterations, tumour formation capacities, and clinical features from sporadic colorectal carcinoma. Most descriptions about tumour biology of CAC refer to ulcerative colitis; data about Crohn´s colitis related carcinomas are scarce. The majority of patients with Crohn´s disease are under immunosuppression which generates a different environment for tumour growth. We first describe the clinical case of a fast growing CAC in a long-term immunosuppressed patient with Crohn´s disease and successful establishment and characterization of carcinoma cell lines along with their corresponding patient-derived xenograft. Subsequently, these tumor models were molecularly and functionally analysed. Beside numerous chromosomal alterations, mutations in TP53, APC, PTEN and SMAD3 were identified. The cell lines express numerous cancer testis antigens, surface molecules involved in immune evasion but low levels of HLA class I molecules. They show strong invasive but in comparison weak migratory activity. The present work is the first description of patient-derived in vitro and in vivo models for CAC from a Crohn´s disease patient. They might be valuable tools for analysis of genetic and epigenetic alterations, biomarker identification, functional testing, including response prediction, and the development of specific therapeutical strategies.

No MeSH data available.


Related in: MedlinePlus

Drug response.Response to therapeutic agents is given as IC50 value (black dot) and clinically evident patient plasma levels are indicated by a line. Therapeutic agents used are listed on the x-axis. On the y-axis, concentrations of the therapeutic agents are displayed in μM using a segmented y-axis.
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f5: Drug response.Response to therapeutic agents is given as IC50 value (black dot) and clinically evident patient plasma levels are indicated by a line. Therapeutic agents used are listed on the x-axis. On the y-axis, concentrations of the therapeutic agents are displayed in μM using a segmented y-axis.

Mentions: Response of the patient-derived cell line HROC69 (in passages 23–29) to therapeutics used for CRC treatment (standard of care or experimentally) was assessed in standard proliferation/cytotoxicity assays (Fig. 5). Taking achievable patient plasma levels as a reference, HROC69 cells were (highly) sensitive towards both 5-FU and Irinotecan, standard chemotherapeutics for CRC treatment. Moreover, HROC69 cells responded to Cisplatin, Taxol, Rapamycin and Gemcitabine. A response to the alkylating agents Temodal, BCNU and CCNU could only be reached using concentrations well above the achievable patient plasma levels. None of the tested therapeutic antibodies–the anti-VEGF antibody Bevacizumab and the anti-EGFR antibody Cetuximab are frequently used in CRC treatment; anti-CD20 Rituximab (in clinical use for treatment of leukaemia) served as a negative control–had any effect on cell viability even at concentration of 20 μg/ml (data not shown). In comparison to other low-passage patient-derived cell lines established in our lab, HROC69 is less sensitive to 5-FU but more sensitive to Cisplatin, Irinotecan, Gemcitabine, Taxol and Rapamycin1720.


Establishment and characterization of HROC69 - a Crohn´s related colonic carcinoma cell line and its matched patient-derived xenograft.

Kuehn F, Mullins CS, Krohn M, Harnack C, Ramer R, Krämer OH, Klar E, Huehns M, Linnebacher M - Sci Rep (2016)

Drug response.Response to therapeutic agents is given as IC50 value (black dot) and clinically evident patient plasma levels are indicated by a line. Therapeutic agents used are listed on the x-axis. On the y-axis, concentrations of the therapeutic agents are displayed in μM using a segmented y-axis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834534&req=5

f5: Drug response.Response to therapeutic agents is given as IC50 value (black dot) and clinically evident patient plasma levels are indicated by a line. Therapeutic agents used are listed on the x-axis. On the y-axis, concentrations of the therapeutic agents are displayed in μM using a segmented y-axis.
Mentions: Response of the patient-derived cell line HROC69 (in passages 23–29) to therapeutics used for CRC treatment (standard of care or experimentally) was assessed in standard proliferation/cytotoxicity assays (Fig. 5). Taking achievable patient plasma levels as a reference, HROC69 cells were (highly) sensitive towards both 5-FU and Irinotecan, standard chemotherapeutics for CRC treatment. Moreover, HROC69 cells responded to Cisplatin, Taxol, Rapamycin and Gemcitabine. A response to the alkylating agents Temodal, BCNU and CCNU could only be reached using concentrations well above the achievable patient plasma levels. None of the tested therapeutic antibodies–the anti-VEGF antibody Bevacizumab and the anti-EGFR antibody Cetuximab are frequently used in CRC treatment; anti-CD20 Rituximab (in clinical use for treatment of leukaemia) served as a negative control–had any effect on cell viability even at concentration of 20 μg/ml (data not shown). In comparison to other low-passage patient-derived cell lines established in our lab, HROC69 is less sensitive to 5-FU but more sensitive to Cisplatin, Irinotecan, Gemcitabine, Taxol and Rapamycin1720.

Bottom Line: They show strong invasive but in comparison weak migratory activity.The present work is the first description of patient-derived in vitro and in vivo models for CAC from a Crohn´s disease patient.They might be valuable tools for analysis of genetic and epigenetic alterations, biomarker identification, functional testing, including response prediction, and the development of specific therapeutical strategies.

View Article: PubMed Central - PubMed

Affiliation: University Medicine Rostock, Department of General-, Thoracic-, Vascular- and Transplantation Surgery, Rostock, Germany.

ABSTRACT
Colitis-associated colorectal cancer (CAC) seems to be a rather unique entity and differs in its genetic alterations, tumour formation capacities, and clinical features from sporadic colorectal carcinoma. Most descriptions about tumour biology of CAC refer to ulcerative colitis; data about Crohn´s colitis related carcinomas are scarce. The majority of patients with Crohn´s disease are under immunosuppression which generates a different environment for tumour growth. We first describe the clinical case of a fast growing CAC in a long-term immunosuppressed patient with Crohn´s disease and successful establishment and characterization of carcinoma cell lines along with their corresponding patient-derived xenograft. Subsequently, these tumor models were molecularly and functionally analysed. Beside numerous chromosomal alterations, mutations in TP53, APC, PTEN and SMAD3 were identified. The cell lines express numerous cancer testis antigens, surface molecules involved in immune evasion but low levels of HLA class I molecules. They show strong invasive but in comparison weak migratory activity. The present work is the first description of patient-derived in vitro and in vivo models for CAC from a Crohn´s disease patient. They might be valuable tools for analysis of genetic and epigenetic alterations, biomarker identification, functional testing, including response prediction, and the development of specific therapeutical strategies.

No MeSH data available.


Related in: MedlinePlus