2024
Pícková, Markéta; Kahounová, Zuzana; Radaszkiewicz, Tomasz; Procházková, Jiřina; Fedr, Radek; Nosková, Michaela; Radaszkiewicz, Katarzyna Anna; Ovesná, Petra; Bryja, Vítězslav; Souček, Karel
Orthotopic model for the analysis of melanoma circulating tumor cells. Journal Article
In: Scientific reports, vol. 14, no. 1, pp. 7827, 2024, ISSN: 2045-2322, (Place: England).
Abstract | Links | BibTeX | Tags: *Melanoma/pathology, *Neoplastic Cells, *Skin Neoplasms/pathology, Animals, Circulating tumor cells, Circulating/pathology, Flow Cytometry, Humans, In vivo model, Lymphatic Metastasis, Melanoma, Metastasis, Tumorectomy
@article{pickova_orthotopic_2024,
title = {Orthotopic model for the analysis of melanoma circulating tumor cells.},
author = {Markéta Pícková and Zuzana Kahounová and Tomasz Radaszkiewicz and Jiřina Procházková and Radek Fedr and Michaela Nosková and Katarzyna Anna Radaszkiewicz and Petra Ovesná and Vítězslav Bryja and Karel Souček},
doi = {10.1038/s41598-024-58236-y},
issn = {2045-2322},
year = {2024},
date = {2024-04-01},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {7827},
abstract = {Metastatic melanoma, a highly lethal form of skin cancer, presents significant clinical challenges due to limited therapeutic options and high metastatic capacity. Recent studies have demonstrated that cancer dissemination can occur earlier, before the diagnosis of the primary tumor. The progress in understanding the kinetics of cancer dissemination is limited by the lack of animal models that accurately mimic disease progression. We have established a xenograft model of human melanoma that spontaneously metastasizes to lymph nodes and lungs. This model allows precise monitoring of melanoma progression and is suitable for the quantitative and qualitative analysis of circulating tumor cells (CTCs). We have validated a flow cytometry-based protocol for CTCs enumeration and isolation. We could demonstrate that (i) CTCs were detectable in the bloodstream from the fourth week after tumor initiation, coinciding with the lymph node metastases appearance, (ii) excision of the primary tumor accelerated the formation of metastases in lymph nodes and lungs as early as one-week post-surgery, accompanied by the increased numbers of CTCs, and (iii) CTCs change their surface protein signature. In summary, we present a model of human melanoma that can be effectively utilized for future drug efficacy studies.},
note = {Place: England},
keywords = {*Melanoma/pathology, *Neoplastic Cells, *Skin Neoplasms/pathology, Animals, Circulating tumor cells, Circulating/pathology, Flow Cytometry, Humans, In vivo model, Lymphatic Metastasis, Melanoma, Metastasis, Tumorectomy},
pubstate = {published},
tppubtype = {article}
}
Metastatic melanoma, a highly lethal form of skin cancer, presents significant clinical challenges due to limited therapeutic options and high metastatic capacity. Recent studies have demonstrated that cancer dissemination can occur earlier, before the diagnosis of the primary tumor. The progress in understanding the kinetics of cancer dissemination is limited by the lack of animal models that accurately mimic disease progression. We have established a xenograft model of human melanoma that spontaneously metastasizes to lymph nodes and lungs. This model allows precise monitoring of melanoma progression and is suitable for the quantitative and qualitative analysis of circulating tumor cells (CTCs). We have validated a flow cytometry-based protocol for CTCs enumeration and isolation. We could demonstrate that (i) CTCs were detectable in the bloodstream from the fourth week after tumor initiation, coinciding with the lymph node metastases appearance, (ii) excision of the primary tumor accelerated the formation of metastases in lymph nodes and lungs as early as one-week post-surgery, accompanied by the increased numbers of CTCs, and (iii) CTCs change their surface protein signature. In summary, we present a model of human melanoma that can be effectively utilized for future drug efficacy studies.
2022
Říhová, Kamila; Dúcka, Monika; Zambo, Iva Staniczková; Vymětalová, Ladislava; Šrámek, Martin; Trčka, Filip; Verner, Jan; Drápela, Stanislav; Fedr, Radek; Suchánková, Tereza; Pavlatovská, Barbora; Ondroušková, Eva; Kubelková, Irena; Zapletalová, Danica; Tuček, Štěpán; Múdry, Peter; Krákorová, Dagmar Adámková; Knopfová, Lucia; Šmarda, Jan; Souček, Karel; Borsig, Lubor; Beneš, Petr
Transcription factor c-Myb: novel prognostic factor in osteosarcoma. Journal Article
In: Clinical & experimental metastasis, vol. 39, no. 2, pp. 375–390, 2022, ISSN: 1573-7276 0262-0898, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: *Bone Neoplasms/pathology, *Osteosarcoma/pathology, Animals, c-Myb, Cell Line, Cell Movement/genetics, Cell Proliferation, Chemoresistance, Gene Expression Regulation, Humans, Metastasis, Mice, Neoplastic, Osteosarcoma, Prognosis, proliferation, Retrospective Studies, Tumor, Wnt Signaling Pathway
@article{rihova_transcription_2022,
title = {Transcription factor c-Myb: novel prognostic factor in osteosarcoma.},
author = {Kamila Říhová and Monika Dúcka and Iva Staniczková Zambo and Ladislava Vymětalová and Martin Šrámek and Filip Trčka and Jan Verner and Stanislav Drápela and Radek Fedr and Tereza Suchánková and Barbora Pavlatovská and Eva Ondroušková and Irena Kubelková and Danica Zapletalová and Štěpán Tuček and Peter Múdry and Dagmar Adámková Krákorová and Lucia Knopfová and Jan Šmarda and Karel Souček and Lubor Borsig and Petr Beneš},
doi = {10.1007/s10585-021-10145-4},
issn = {1573-7276 0262-0898},
year = {2022},
date = {2022-04-01},
journal = {Clinical & experimental metastasis},
volume = {39},
number = {2},
pages = {375–390},
abstract = {The transcription factor c-Myb is an oncoprotein promoting cell proliferation and survival when aberrantly activated/expressed, thus contributing to malignant transformation. Overexpression of c-Myb has been found in leukemias, breast, colon and adenoid cystic carcinoma. Recent studies revealed its expression also in osteosarcoma cell lines and suggested its functional importance during bone development. However, the relevance of c-Myb in control of osteosarcoma progression remains unknown. A retrospective clinical study was carried out to assess a relationship between c-Myb expression in archival osteosarcoma tissues and prognosis in a cohort of high-grade osteosarcoma patients. In addition, MYB was depleted in metastatic osteosarcoma cell lines SAOS-2 LM5 and 143B and their growth, chemosensitivity, migration and metastatic activity were determined. Immunohistochemical analysis revealed that high c-Myb expression was significantly associated with poor overall survival in the cohort and metastatic progression in young patients. Increased level of c-Myb was detected in metastatic osteosarcoma cell lines and its depletion suppressed their growth, colony-forming capacity, migration and chemoresistance in vitro in a cell line-dependent manner. MYB knock-out resulted in reduced metastatic activity of both SAOS-2 LM5 and 143B cell lines in immunodeficient mice. Transcriptomic analysis revealed the c-Myb-driven functional programs enriched for genes involved in the regulation of cell growth, stress response, cell adhesion and cell differentiation/morphogenesis. Wnt signaling pathway was identified as c-Myb target in osteosarcoma cells. Taken together, we identified c-Myb as a negative prognostic factor in osteosarcoma and showed its involvement in the regulation of osteosarcoma cell growth, chemosensitivity, migration and metastatic activity.},
note = {Place: Netherlands},
keywords = {*Bone Neoplasms/pathology, *Osteosarcoma/pathology, Animals, c-Myb, Cell Line, Cell Movement/genetics, Cell Proliferation, Chemoresistance, Gene Expression Regulation, Humans, Metastasis, Mice, Neoplastic, Osteosarcoma, Prognosis, proliferation, Retrospective Studies, Tumor, Wnt Signaling Pathway},
pubstate = {published},
tppubtype = {article}
}
The transcription factor c-Myb is an oncoprotein promoting cell proliferation and survival when aberrantly activated/expressed, thus contributing to malignant transformation. Overexpression of c-Myb has been found in leukemias, breast, colon and adenoid cystic carcinoma. Recent studies revealed its expression also in osteosarcoma cell lines and suggested its functional importance during bone development. However, the relevance of c-Myb in control of osteosarcoma progression remains unknown. A retrospective clinical study was carried out to assess a relationship between c-Myb expression in archival osteosarcoma tissues and prognosis in a cohort of high-grade osteosarcoma patients. In addition, MYB was depleted in metastatic osteosarcoma cell lines SAOS-2 LM5 and 143B and their growth, chemosensitivity, migration and metastatic activity were determined. Immunohistochemical analysis revealed that high c-Myb expression was significantly associated with poor overall survival in the cohort and metastatic progression in young patients. Increased level of c-Myb was detected in metastatic osteosarcoma cell lines and its depletion suppressed their growth, colony-forming capacity, migration and chemoresistance in vitro in a cell line-dependent manner. MYB knock-out resulted in reduced metastatic activity of both SAOS-2 LM5 and 143B cell lines in immunodeficient mice. Transcriptomic analysis revealed the c-Myb-driven functional programs enriched for genes involved in the regulation of cell growth, stress response, cell adhesion and cell differentiation/morphogenesis. Wnt signaling pathway was identified as c-Myb target in osteosarcoma cells. Taken together, we identified c-Myb as a negative prognostic factor in osteosarcoma and showed its involvement in the regulation of osteosarcoma cell growth, chemosensitivity, migration and metastatic activity.
2021
Kvokačková, Barbora; Remšík, Ján; Jolly, Mohit Kumar; Souček, Karel
Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial-Mesenchymal Plasticity. Journal Article
In: Cancers, vol. 13, no. 9, 2021, ISSN: 2072-6694, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: epithelial–mesenchymal transition, mesenchymal–epithelial transition, Metastasis, Plasticity, triple-negative breast cancer
@article{kvokackova_phenotypic_2021,
title = {Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial-Mesenchymal Plasticity.},
author = {Barbora Kvokačková and Ján Remšík and Mohit Kumar Jolly and Karel Souček},
doi = {10.3390/cancers13092188},
issn = {2072-6694},
year = {2021},
date = {2021-05-01},
journal = {Cancers},
volume = {13},
number = {9},
abstract = {Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial-mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal-epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer.},
note = {Place: Switzerland},
keywords = {epithelial–mesenchymal transition, mesenchymal–epithelial transition, Metastasis, Plasticity, triple-negative breast cancer},
pubstate = {published},
tppubtype = {article}
}
Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial-mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal-epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer.
2020
Muresan, Ximena Maria; Bouchal, Jan; Culig, Zoran; Souček, Karel
Toll-Like Receptor 3 in Solid Cancer and Therapy Resistance. Journal Article
In: Cancers, vol. 12, no. 11, 2020, ISSN: 2072-6694, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: cytokines, dsRNA, Metastasis, therapy resistance, toll-like receptor 3
@article{muresan_toll-like_2020,
title = {Toll-Like Receptor 3 in Solid Cancer and Therapy Resistance.},
author = {Ximena Maria Muresan and Jan Bouchal and Zoran Culig and Karel Souček},
doi = {10.3390/cancers12113227},
issn = {2072-6694},
year = {2020},
date = {2020-11-01},
journal = {Cancers},
volume = {12},
number = {11},
abstract = {Toll-like receptor 3 (TLR3) is a member of the TLR family, which has been extensively studied for its antiviral function. It is highly expressed in the endosomes of antigen-presenting immune cells and epithelial cells. TLR3 binds specifically double-strand RNAs (dsRNAs), leading to the activation of mainly two downstream pathways: the phosphorylation of IRF3, with subsequent production of type I interferon, and the activation of NF-κB, which drives the production of inflammatory cytokines and chemokines. Several studies have demonstrated TLR3 expression in multiple neoplasia types including breast, prostate, and lung cancer. Most studies were focused on the beneficial role of TLR3 activation in tumor cells, which leads to the production of cytotoxic cytokines and interferons and promotes caspase-dependent apoptosis. Indeed, ligands of this receptor were proposed for the treatment of cancer, also in combination with conventional chemotherapy. In contrast to these findings, recent evidence showed a link between TLR3 and tumor progression, metastasis, and therapy resistance. In the present review, we summarize the current knowledge of the mechanisms through which TLR3 can either lead to tumor regression or promote carcinogenesis as well as the potential of TLR-based therapies in resistant cancer.},
note = {Place: Switzerland},
keywords = {cytokines, dsRNA, Metastasis, therapy resistance, toll-like receptor 3},
pubstate = {published},
tppubtype = {article}
}
Toll-like receptor 3 (TLR3) is a member of the TLR family, which has been extensively studied for its antiviral function. It is highly expressed in the endosomes of antigen-presenting immune cells and epithelial cells. TLR3 binds specifically double-strand RNAs (dsRNAs), leading to the activation of mainly two downstream pathways: the phosphorylation of IRF3, with subsequent production of type I interferon, and the activation of NF-κB, which drives the production of inflammatory cytokines and chemokines. Several studies have demonstrated TLR3 expression in multiple neoplasia types including breast, prostate, and lung cancer. Most studies were focused on the beneficial role of TLR3 activation in tumor cells, which leads to the production of cytotoxic cytokines and interferons and promotes caspase-dependent apoptosis. Indeed, ligands of this receptor were proposed for the treatment of cancer, also in combination with conventional chemotherapy. In contrast to these findings, recent evidence showed a link between TLR3 and tumor progression, metastasis, and therapy resistance. In the present review, we summarize the current knowledge of the mechanisms through which TLR3 can either lead to tumor regression or promote carcinogenesis as well as the potential of TLR-based therapies in resistant cancer.
2013
Vaňhara, Petr; Souček, Karel
Mutual cytokine crosstalk between colon cancer cells and microenvironment initiates development of distant metastases. Journal Article
In: JAK-STAT, vol. 2, no. 2, pp. e23810, 2013, ISSN: 2162-3988 2162-3996, (Place: United States).
Abstract | Links | BibTeX | Tags: dissemination, interleukin 11, Metastasis, metastatic niche, microenvironment, transforming growth factor-β, tumor stroma
@article{vanhara_mutual_2013,
title = {Mutual cytokine crosstalk between colon cancer cells and microenvironment initiates development of distant metastases.},
author = {Petr Vaňhara and Karel Souček},
doi = {10.4161/jkst.23810},
issn = {2162-3988 2162-3996},
year = {2013},
date = {2013-04-01},
journal = {JAK-STAT},
volume = {2},
number = {2},
pages = {e23810},
abstract = {Tumor growth and cancer development are considered clear examples of Darwinian selection, whereby random mutational events in heterogeneous cancer cell populations that best fit the selective microenvironment are preferred.(1) As a result, cancer cells evolve resistance to apoptosis, hide from immune surveillance and acquire the ability to invade other organs. Cancer cells, however, are not necessarily passive subjects of selection; they can actively subvert the host tissue to provide a favorable habitat for their growth. Recent findings by Calon et al. convincingly demonstrate that transforming growth factor-β-induced secretion of interleukin 11 by tumor stromal fibroblasts is a necessary prerequisite for the development of distant metastases in colorectal carcinoma. Thus, understanding the complex molecular feedback loops between cancer cells and the surrounding microenvironment (i.e., the tumor-associated stroma or invaded host tissue) should aid the identification of useful molecular targets for improving clinical management of advanced metastatic cancers.},
note = {Place: United States},
keywords = {dissemination, interleukin 11, Metastasis, metastatic niche, microenvironment, transforming growth factor-β, tumor stroma},
pubstate = {published},
tppubtype = {article}
}
Tumor growth and cancer development are considered clear examples of Darwinian selection, whereby random mutational events in heterogeneous cancer cell populations that best fit the selective microenvironment are preferred.(1) As a result, cancer cells evolve resistance to apoptosis, hide from immune surveillance and acquire the ability to invade other organs. Cancer cells, however, are not necessarily passive subjects of selection; they can actively subvert the host tissue to provide a favorable habitat for their growth. Recent findings by Calon et al. convincingly demonstrate that transforming growth factor-β-induced secretion of interleukin 11 by tumor stromal fibroblasts is a necessary prerequisite for the development of distant metastases in colorectal carcinoma. Thus, understanding the complex molecular feedback loops between cancer cells and the surrounding microenvironment (i.e., the tumor-associated stroma or invaded host tissue) should aid the identification of useful molecular targets for improving clinical management of advanced metastatic cancers.