Publications by authors named "Udo Schumacher"

233 Publications

Fra-2 overexpression upregulates pro-metastatic cell-adhesion molecules, promotes pulmonary metastasis, and reduces survival in a spontaneous xenograft model of human breast cancer.

J Cancer Res Clin Oncol 2021 Oct 24. Epub 2021 Oct 24.

Institute of Anatomy and Experimental Morphology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Purpose: The transcription factor Fra-2 affects the invasive potential of breast cancer cells by dysregulating adhesion molecules in vitro. Previous results suggested that it upregulates the expression of E- and P-selectin ligands. Such selectin ligands are important members of the leukocyte adhesion cascade, which govern the adhesion and transmigration of cancer cells into the stroma of the host organ of metastasis. As so far, no in vivo data are available, this study was designed to elucidate the role of Fra-2 expression in a spontaneous breast cancer metastasis xenograft model.

Methods: The effect of Fra-2 overexpression in two stable Fra-2 overexpressing clones of the human breast cancer cell line MDA MB231 on survival and metastatic load was studied after subcutaneous injection into scid and E- and P-selectin-deficient scid mice.

Results: Fra-2 overexpression leads to a significantly shorter overall survival and a higher amount of spontaneous lung metastases not only in scid mice, but also in E- and P-deficient mice, indicating that it regulates not only selectin ligands, but also selectin-independent adhesion processes.

Conclusion: Thus, Fra-2 expression influences the metastatic potential of breast cancer cells by changing the expression of adhesion molecules, resulting in increased adherence to endothelial cells in a breast cancer xenograft model.
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http://dx.doi.org/10.1007/s00432-021-03812-2DOI Listing
October 2021

Low expression of CD24 is associated with poor survival in colorectal cancer.

Biochimie 2021 Oct 9. Epub 2021 Oct 9.

Faculty of Biology and Biotechnology, HSE University, Moscow, Russia; SRC Bioclinicum, Moscow, Russia. Electronic address:

In this study we analyzed expression of CD24 in a cohort of colorectal cancer patients using immunohistochemistry staining of CD24. We found a significant association between absence or low expression of CD24 (10% of membranous and 55% of cytoplasmic staining) and shortened patient survival. Protein localization played a crucial role in the prognosis: membranous form was the major and prognostic one in primary tumors, while cytoplasmic expression was elevated in liver metastases compared to the primary tumors and contained prognostic information. Then, using The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) RNA-seq data, we showed that CD24 mRNA level was two-fold decreased in primary colorectal cancers compared to adjacent normal mucosa. Like the protein staining data, ten percent of patients with the lowest mRNA expression levels of CD24 in primary tumors had reduced survival compared to the ones with higher expression. To explain these findings mechanistically, shRNA-mediated CD24 knockdown was performed in HT-29 colorectal cancer cells. It resulted in the increase of cell migration in vitro, no changes in proliferation and apoptosis, and a slight decrease in cell invasion. As increased cell migration is a hallmark of metastasis formation, this finding corroborates the association of a decreased CD24 expression with poor prognosis. Differential gene expression analysis revealed upregulation of genes involved in cell migration in the group of patients with low CD24 expression, including integrin subunit α3 and α3, β3 subunits of laminin 332. Further co-expression analysis identified SPI1, STAT1 and IRF1 transcription factors as putative master-regulators in this group.
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http://dx.doi.org/10.1016/j.biochi.2021.10.004DOI Listing
October 2021

YKL-40 protein expression in human tumor samples and human tumor cell line xenografts: implications for its use in tumor models.

Cell Oncol (Dordr) 2021 Oct 25;44(5):1183-1195. Epub 2021 Aug 25.

Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: YKL-40, also known as non-enzymatic chitinase-3 like-protein-1 (CHI3L1), is a glycoprotein expressed and secreted mainly by inflammatory cells and tumor cells. Accordingly, several studies demonstrated elevated YKL-40 serum levels in cancer patients and found YKL-40 to be correlated with a poor prognosis and disease severity in some tumor entities. YKL-40 was suggested to be involved in angiogenesis and extracellular matrix remodeling. As yet, however, its precise biological function remains elusive.

Methods: As YKL-40 protein expression has only been investigated in few malignancies, we employed immunohistochemical detection in a large multi-tumor tissue microarray consisting of 2,310 samples from 72 different tumor entities. In addition, YKL-40 protein expression was determined in primary mouse xenograft tumors derived from human cancer cell lines.

Results: YKL-40 could be detected in almost all cancer entities and was differently expressed depending on tumor stage and subtype (e.g., thyroid cancer, colorectal cancer, gastric cancer and ovarian cancer). While YKL-40 was absent in in vitro grown human cancer cell lines, YKL-40 expression was upregulated in xenograft tumor tissues in vivo.

Conclusions: These data provide new insights into YKL-40 expression at the protein level in various tumor entities and its regulation in tumor models. Our data suggest that upregulation of YKL-40 expression is a common feature in vivo and is finely regulated by tumor cell-microenvironment interactions.
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http://dx.doi.org/10.1007/s13402-021-00630-zDOI Listing
October 2021

TGFB-induced factor homeobox 1 (TGIF) expression in breast cancer.

BMC Cancer 2021 Aug 14;21(1):920. Epub 2021 Aug 14.

Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Background: Breast cancer (BC) is the most frequent female cancer and preferentially metastasizes to bone. The transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism. However, it is not yet known whether TGIF is associated with BC bone metastasis or patient outcome and thus of potential interest.

Methods: TGIF expression was analyzed by immunohistochemistry in 1197 formalin-fixed, paraffin-embedded tissue samples from BC patients treated in the GAIN (German Adjuvant Intergroup Node-Positive) study with two adjuvant dose-dense schedules of chemotherapy with or without bisphosphonate ibandronate. TGIF expression was categorized into negative/low and moderate/strong staining. Endpoints were disease-free survival (DFS), overall survival (OS) and time to primary bone metastasis as first site of relapse (TTPBM).

Results: We found associations of higher TGIF protein expression with smaller tumor size (p = 0.015), well differentiated phenotype (p < 0.001) and estrogen receptor (ER)-positive BC (p < 0.001). Patients with higher TGIF expression levels showed a significantly longer disease-free (DFS: HR 0.75 [95%CI 0.59-0.95], log-rank p = 0.019) and overall survival (OS: HR 0.69 [95%CI 0.50-0.94], log-rank p = 0.019), but no association with TTPBM (HR 0.77 [95%CI 0.51-1.16]; p = 0.213). Univariate analysis in molecular subgroups emphasized that elevated TGIF expression was prognostic for both DFS and OS in ER-positive BC patients (DFS: HR 0.68 [95%CI 0.51-0.91]; log-rank p = 0.009, interaction p = 0.130; OS: HR 0.60 [95%CI 0.41-0.88], log-rank p = 0.008, interaction p = 0.107) and in the HER2-negative subgroup (DFS:HR 0.67 [95%CI 0.50-0.88], log-rank p = 0.004, interaction p = 0.034; OS: HR 0.57 [95%CI 0.40-0.81], log-rank p = 0.002, interaction p = 0.015).

Conclusions: Our results suggest that moderate to high TGIF expression is a common feature of breast cancer cells and that this is not associated with bone metastases as first site of relapse. However, a reduced expression is linked to tumor progression, especially in HER2-negative breast cancer.

Trial Registration: This clinical trial has been registered with ClinicalTrials.gov ; registration number: NCT00196872 .
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http://dx.doi.org/10.1186/s12885-021-08656-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364691PMC
August 2021

Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression.

J Exp Clin Cancer Res 2021 Jun 26;40(1):214. Epub 2021 Jun 26.

Institute of Anatomy and Experimental Morphology, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Mesothelial E- and P-selectins substantially mediate the intraperitoneal spread of Pancreatic ductal adenocarcinoma (PDA) cells in xenograft models. In the absence of selectins in the host, the integrin subunit alpha-V (ITGAV, CD51) was upregulated in the remaining metastatic deposits. Here we present the first experimental study to investigate if ITGAV plays a functional role in PDA tumor growth and progression with a particular focus on intraperitoneal carcinomatosis.

Methods: Knockdown of ITGAV was generated using an RNA interference-mediated approach in two PDA cell lines. Tumor growth, intraperitoneal and distant metastasis were analyzed in a xenograft model. Cell lines were characterized in vitro. Gene expression of the xenograft tumors was analyzed. Patient samples were histologically classified and associations to survival were evaluated.

Results: The knockdown of ITGAV in PDA cells strongly reduces primary tumor growth, peritoneal carcinomatosis and spontaneous pulmonary metastasis. ITGAV activates latent TGF-β and thereby drives epithelial-mesenchymal transition. Combined depletion of ITGAV on the tumor cells and E- and P-selectins in the tumor-host synergistically almost abolishes intraperitoneal spread. Accordingly, high expression of ITGAV in PDA cells was associated with reduced survival in patients.

Conclusion: Combined depletion of ITGAV in PDA cells and E- and P-selectins in host mice massively suppresses intraperitoneal carcinomatosis of PDA cells xenografted into immunodeficient mice, confirming the hypothesis of a partly redundant adhesion cascade of metastasizing cancer cells. Our data strongly encourage developing novel therapeutic approaches for the combined targeting of E- and P-selectins and ITGAV in PDA.
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http://dx.doi.org/10.1186/s13046-021-01946-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235815PMC
June 2021

Effect of the Expression of and Genes on the Metastatic Potential of Breast Cancer Cells.

Front Genet 2021 2;12:662843. Epub 2021 Jun 2.

Faculty of Biology and Biotechnologies, National Research University Higher School of Economics, Moscow, Russia.

Breast cancer (BC) is the leading cause of death from malignant neoplasms among women worldwide, and metastatic BC presents the biggest problems for treatment. Previously, it was shown that lower expression of and genes is associated with a higher risk of the formation of distant metastases in BC. In this work, we studied the change in phenotypical traits, as well as in the transcriptomic and proteomic profiles of BC cells as a result of the stable knockdown of and genes. The knockdown of and genes was found to lead to a strong increase in the expression of the matrix metalloproteinase (MMP) . These results were in good agreement with the correlation analysis of gene expression in tumor samples from patients and were additionally confirmed by zymography. The knockdown of and genes was also discovered to change the expression of a group of genes involved in the formation of intercellular contacts. In particular, the expression of the gene was markedly reduced, which also complies with the correlation analysis. The spheroid formation assay showed that intercellular adhesion decreased as a result of the knockdown of the and genes. Thus, the obtained data indicate that malignant breast tumors with reduced expression of the and genes can metastasize with a higher probability due to a more efficient invasion of tumor cells.
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http://dx.doi.org/10.3389/fgene.2021.662843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206645PMC
June 2021

Molecular characteristics and tumorigenicity of ascites-derived tumor cells: mitochondrial oxidative phosphorylation as a novel therapy target in ovarian cancer.

Mol Oncol 2021 Jun 1. Epub 2021 Jun 1.

Department of Gynecology, University Medical Center Hamburg-Eppendorf, Germany.

Ovarian cancer disseminates primarily intraperitoneally. Detached tumor cell aggregates (spheroids) from the primary tumor are regarded as 'metastatic units' that exhibit a low sensitivity to classical chemotherapy, probably due to their unique molecular characteristics. We have analyzed the cellular composition of ascites from OvCa patients, using flow cytometry, and studied their behavior in vitro and in vivo. We conclude that ascites-derived cultured cells from OvCa patients give rise to two subpopulations: adherent cells and non-adherent cells. Here, we found that the AD population includes mainly CD90 cells with highly proliferative rates in vitro but no tumorigenic potential in vivo, whereas the NAD population contains principally tumor cell spheroids (EpCAM /CD24 ) with low proliferative potential in vitro. Enriched tumor cell spheroids from the ascites of high-grade serous OvCA patients, obtained using cell strainers, were highly tumorigenic in vivo and their metastatic spread pattern precisely resembled the tumor dissemination pattern found in the corresponding patients. Comparative transcriptome analyses from ascites-derived tumor cell spheroids (n = 10) versus tumor samples from different metastatic sites (n = 30) revealed upregulation of genes involved in chemoresistance (TGM1, HSPAs, MT1s), cell adhesion and cell-barrier integrity (PKP3, CLDNs, PPL), and the oxidative phosphorylation process. Mitochondrial markers (mass and membrane potential) showed a reduced mitochondrial function in tumoroids from tumor tissue compared with ascites-derived tumor spheroids in flow cytometry analysis. Interestingly, response to OXPHOS inhibition by metformin and IACS010759 in tumor spheroids correlated with the extent of mitochondrial membrane potential measured by fluorescence-activated cell sorting. Our data contribute to a better understanding of the biology of ovarian cancer spheroids and identify the OXPHOS pathway as new potential treatment option in advanced ovarian cancer.
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http://dx.doi.org/10.1002/1878-0261.13028DOI Listing
June 2021

Infiltration of Immune Competent Cells into Primary Tumors and Their Surrounding Connective Tissues in Xenograft and Syngeneic Mouse Models.

Int J Mol Sci 2021 Apr 19;22(8). Epub 2021 Apr 19.

Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.

To fight cancer more efficiently with cell-based immunotherapy, more information about the cells of the immune system and their interaction with cancer cells in vivo is needed. Therefore paraffin wax embedded primary breast cancers from the syngeneic mouse WAP-T model and from xenografted tumors of breast, colon, melanoma, ovarian, neuroblastoma, pancreatic, prostate, and small cell lung cancer were investigated for the infiltration of immunocompetent cells by immunohistochemistry using antibodies against leukocyte markers. The following markers were used: CD45 as a pan-leukocyte marker, BSA-I as a dendritic cell marker, CD11b as an NK cell marker, and CD68 as a marker for macrophages. The labeled immune cells were attributed to the following locations: adjacent adipose tissue, tumor capsule, intra-tumoral septae, and cancer cells directly. In xenograft tumors, the highest score of CD45 and CD11b positive, NK, and dendritic cells were found in the adjacent adipose tissue, followed by lesser infiltration directly located at the cancer cells themselves. The detected numbers of CD45 positive cells differed between the tumor entities: few infiltrating cells in breast cancer, small cell lung cancer, neuroblastoma, a moderate infiltration in colon cancer, melanoma and ovarian cancer, strongest infiltration in prostate and pancreatic cancer. In the syngeneic tumors, the highest score of CD45 and CD11b positive, NK and dendritic cells were observed in the tumor capsule, followed by a lesser infiltration of the cancer tissue. Our findings argue for paying more attention to investigate how immune-competent cells can reach the tumor cells directly.
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http://dx.doi.org/10.3390/ijms22084213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073739PMC
April 2021

Analyzing tyrosine kinase activity in head and neck cancer by functional kinomics: Identification of hyperactivated Src family kinases as prognostic markers and potential targets.

Int J Cancer 2021 09 7;149(5):1166-1180. Epub 2021 May 7.

Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Signal transduction via protein kinases is of central importance in cancer biology and treatment. However, the clinical success of kinase inhibitors is often hampered by a lack of robust predictive biomarkers, which is also caused by the discrepancy between kinase expression and activity. Therefore, there is a need for functional tests to identify aberrantly activated kinases in individual patients. Here we present a systematic analysis of the tyrosine kinases in head and neck cancer using such a test-functional kinome profiling. We detected increased tyrosine kinase activity in tumors compared with their corresponding normal tissue. Moreover, we identified members of the family of Src kinases (Src family kinases [SFK]) to be aberrantly activated in the majority of the tumors, which was confirmed by additional methods. We could also show that SFK hyperphosphorylation is associated with poor prognosis, while inhibition of SFK impaired cell proliferation, especially in cells with hyperactive SFK. In summary, functional kinome profiling identified SFK to be frequently hyperactivated in head and neck squamous cell carcinoma. SFK may therefore be potential therapeutic targets. These results furthermore demonstrate how functional tests help to increase our understanding of cancer biology and support the expansion of precision oncology.
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http://dx.doi.org/10.1002/ijc.33606DOI Listing
September 2021

Opposing prognostic relevance of junction plakoglobin in distinct prostate cancer patient subsets.

Mol Oncol 2021 Jul 17;15(7):1956-1969. Epub 2021 Feb 17.

Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Germany.

Both oncogenic and tumor suppressor functions have been described for junction plakoglobin (JUP), also known as γ-catenin. To clarify the role of JUP in prostate cancer, JUP protein expression was immunohistochemically detected in a tissue microarray containing 11 267 individual prostatectomy specimens. Considering all patients, high JUP expression was associated with adverse tumor stage (P = 0.0002), high Gleason grade (P < 0.0001), and lymph node metastases (P = 0.011). These associations were driven mainly by the subset without TMPRSS2:ERG fusion, in which high JUP expression was an independent predictor of poor prognosis (multivariate analyses, P = 0.0054) and early biochemical recurrence (P = 0.0003). High JUP expression was further linked to strong androgen receptor expression (P < 0.0001), high cell proliferation, and PTEN and FOXP1 deletion (P < 0.0001). In the ERG-negative subset, high JUP expression was additionally linked to MAP3K7 (P = 0.0007) and CHD1 deletion (P = 0.0021). Contrasting the overall prognostic effect of JUP, low JUP expression indicated poor prognosis in the fraction of CHD1-deleted patients (P = 0.039). In this subset, the association of high JUP and high cell proliferation was specifically absent. In conclusion, the controversial biological roles of JUP are reflected by antagonistic prognostic effects in distinct prostate cancer patient subsets.
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http://dx.doi.org/10.1002/1878-0261.12922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253102PMC
July 2021

Diagnostic yield of cone beam computed tomography for small foreign body detection in the hand in comparison with radiography, MSCT and MRI: an ex vivo study.

Injury 2021 Jan 15. Epub 2021 Jan 15.

Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Introduction: Detection of symptomatic foreign bodies (FB) after penetrating hand injuries can be challenging. Multiplanar radiography is most frequently used for FB detection and may be complemented by multislice computed tomography (MSCT) if suspected FBs cannot be identified and clinical symptoms are persisting. Cone beam computed tomography (CBCT) is a promising imaging modality for traumatology aside from fracture detection. The aim of this study was to evaluate the diagnostic yield of CBCT for different small FBs in the hand in comparison with radiography, MSCT and magnetic resonance imaging (MRI).

Methods: In ten cadaveric hands of voluntary body donors, 20 different FBs (metal, glass, stone, wood, thorn) in predefined sizes (0.5, 1 and 2mm) were randomly placed in the central hand and the basal phalanges. All hands were imaged using radiography, 256-slice CT, CBCT, and 3T MRI. A total of 200 subcutaneous and intramuscular particles were analyzed for their visibility by two observers at two time points. The Cohens Kappa coefficient was calculated as a measure of interobserver agreement and intraobserver reliability. The particle detection rate between different imaging modalities was compared using McNemar Chi-tests.

Results: CBCT and MSCT provided a higher detection rate (94.6% and 86.3%) for detecting metal, glass and stone particles compared to standard radiography (70.0%; each p<0.001). MRI did not provide a diagnostic benefit. Wood particles and thorns were not reliably recognizable by any imaging technique. The interobserver agreement (K=0.768; p<0.001) and the intraobserver reliability for both observers (K=0.914 and K=0.907; p<0.001) were good. The dose length product (DLP) was 2-fold lower in CBCT than in MSCT (39.2 ± 2.1 vs. 81.4 ± 2.9 mGy*cm; p<0.001).

Conclusions: In this ex vivo study, CBCT provided a high detection rate for small metal, glass, and stone particles while the radiation exposure was significantly lower compared to MSCT. These results suggest that CBCT instead of MSCT seems a reasonable option in supplementary diagnostics to exclude of FBs. The primary use of CBCT instead of radiography may be considered for symptomatic patients with expected small radiopaque particles <1mm. Organic FBs can be visualized indirectly in MRI and CBCT/MSCT by entrapped surrounding air.

Level Of Evidence: Level I, diagnostic study.
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http://dx.doi.org/10.1016/j.injury.2021.01.017DOI Listing
January 2021

CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo.

Cancer Gene Ther 2021 Jan 7. Epub 2021 Jan 7.

Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

The outcome of prostate cancer (PCa) patients is highly variable and depends on whether or not distant metastases occur. Multiple chromosomal deletions have been linked to early tumor marker PSA recurrence (biochemical relapse, BCR) after radical prostatectomy (RP), but their potential role for distant metastasis formation is largely unknown. Here, we specifically analyzed whether deletion of the tumor suppressor CHD1 (5q21) influences the post-surgical risk of distant metastasis and whether CHD1 loss directly contributes to metastasis formation in vivo. By considering >6800 patients we found that the CHD1 deletion negatively influences metastasis-free survival in R0 patients (HR: 2.32; 95% CI: 1.61, 3.33; p < 0.001) independent of preoperative PSA, pT stage, pN status, Gleason Score, and BCR. Moreover, CHD1 deletion predicts shortened BCR-free survival in pT2 patients and cancer-specific survival in all patients. In vivo, CHD1 loss increases spontaneous pulmonary metastasis formation in two distinct PCa models coupled with a higher number of multicellular colonies as compared to single-cell metastases. Transcriptome analyses revealed down-regulation of the PCa-specific metastasis suppressor and TGFβ signaling regulator PMEPA1 after CHD1 depletion in both tested PCa models. CHD1 loss increases the risk of postoperative metastasis in R0-resected PCa patients and promotes spontaneous metastasis formation in vivo.
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http://dx.doi.org/10.1038/s41417-020-00288-zDOI Listing
January 2021

Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Knockout Mice.

Front Physiol 2020 12;11:597559. Epub 2020 Nov 12.

Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Chronic hypoxia causes pulmonary vasoconstriction leading to pulmonary hypertension and right ventricular hypertrophy. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis; its level increases in hypoxia (HX) concomitantly with reduced activity of dimethylarginine dimethylaminohydrolases (DDAH-1 and DDAH-2), enzymes metabolizing ADMA. Ddah1 knockout (KO) mice may therefore help to understand the pathophysiological roles of this enzyme and its substrate, ADMA, in the development of hypoxia-associated pulmonary hypertension. Ddah1 KO mice and their wild-type (WT) littermates were subjected to normoxia (NX) or for 21 days. We measured ADMA concentration in plasma and lungs, DDAH1 and DDAH2 mRNA and protein expression in the lungs, right ventricular systolic pressure (RVSP), right ventricular hypertrophy by the Fulton index, and cardiomyocyte hypertrophy by dystrophin staining of the heart. Ddah1 KO mice had higher ADMA concentrations in plasma and in lung tissue than WT in NX ( < 0.05). ADMA significantly increased in WT-HX in plasma and lungs, while there were no significant differences in WT-HX vs. KO-HX. This finding was paralleled by a 38 ± 13% reduction in Ddah1 but not Ddah2 mRNA expression, and reduced DDAH1 protein expression but stable DDAH2 protein levels in WT mice. Ddah1 KO mice showed significant elevation of DDAH2 protein but not mRNA levels, which further increased in HX. HX led to increased RVSP and right ventricular hypertrophy in both, WT and KO mice, with no significant differences between both genotypes. Chronic hypoxia causes an elevation of ADMA, which may impair NO production and lead to endothelial dysfunction and vasoconstriction. Downregulation of DDAH1 expression and activity may be involved in this; however, knockout of the Ddah1 gene does not modify the hypoxia-induced pathophysiological changes of pulmonary blood pressure and right ventricular hypertrophy, possibly due to compensatory upregulation of DDAH2 protein.
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http://dx.doi.org/10.3389/fphys.2020.597559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689360PMC
November 2020

Piezo1 Inactivation in Chondrocytes Impairs Trabecular Bone Formation.

J Bone Miner Res 2021 02 12;36(2):369-384. Epub 2020 Nov 12.

Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The skeleton is a dynamic tissue continuously adapting to mechanical stimuli. Although matrix-embedded osteocytes are considered as the key mechanoresponsive bone cells, all other skeletal cell types are principally exposed to macroenvironmental and microenvironmental mechanical influences that could potentially affect their activities. It was recently reported that Piezo1, one of the two mechanically activated ion channels of the Piezo family, functions as a mechanosensor in osteoblasts and osteocytes. Here we show that Piezo1 additionally plays a critical role in the process of endochondral bone formation. More specifically, by targeted deletion of Piezo1 or Piezo2 in either osteoblast (Runx2Cre) or osteoclast lineage cells (Lyz2Cre), we observed severe osteoporosis with numerous spontaneous fractures specifically in Piezo1 mice. This phenotype developed at an early postnatal stage and primarily affected the formation of the secondary spongiosa. The presumptive Piezo1 osteoblasts in this region displayed an unusual flattened appearance and were positive for type X collagen. Moreover, transcriptome analyses of primary osteoblasts identified an unexpected induction of chondrocyte-related genes in Piezo1 cultures. Because Runx2 is not only expressed in osteoblast progenitor cells, but also in prehypertrophic chondrocytes, these data suggested that Piezo1 functions in growth plate chondrocytes to ensure trabecular bone formation in the process of endochondral ossification. To confirm this hypothesis, we generated mice with Piezo1 deletion in chondrocytes (Col2a1Cre). These mice essentially recapitulated the phenotype of Piezo1 animals, because they displayed early-onset osteoporosis with multiple fractures, as well as impaired formation of the secondary spongiosa with abnormal osteoblast morphology. Our data identify a previously unrecognized key function of Piezo1 in endochondral ossification, which, together with its role in bone remodeling, suggests that Piezo1 represents an attractive target for the treatment of skeletal disorders. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4198DOI Listing
February 2021

Absence of convection in solid tumors caused by raised interstitial fluid pressure severely limits success of chemotherapy-a numerical study in cancers.

Math Biosci Eng 2020 09;17(5):6128-6148

Competence Center Bioinformatics, Institute for Applied Computer Science, University of Applied Sciences Stralsund, Zur Schwedenschanze 15, 18435 Stralsund, Germany.

In comparison with lymphomas and leukemias, chemotherapy of solid neoplasms, i.e., cancer, has much more limited success in curing the patient. This lack of efficacy of chemotherapy has been attributed to increased interstitial fluid pressure within cancers, which obstructs convection and only permits diffusion of oxygen and nutrients about 100 μm from blood vessels. As diffusion is limited to this distance, hypoxic and necrotic fractions within the tumor are observed beyond this region. The comparably small number of cancer cells that can be targeted with drugs inevitably leads to an ineffective treatment response. This study presents an analysis of the influence of interstitial fluid pressure on the chemotherapeutic effect in an HT29 human colon cancer xenograft mouse tumor model. To investigate the limited distribution of drugs into primary tumor and metastases, we developed a mathematical model describing tumor growth dynamics of oxygenated, hypoxic, and necrotic fractions, combined with a pharmacokinetic-pharmacodynamic model describing the behavior and effectivity of the chemotherapeutic agent. According to the numerical simulations, the age of the tumor at treatment was the decisive factor in the reduction in size of the primary tumor. This effect is mediated by the rapid decrease in the percentage of oxygenated cells within the tumor, which reduces the fraction of cells that can be affected by the drug. As in the primary tumor, interstitial fluid pressure builds up in metastases when they reach a specific size, leading to the formation of tumor fractions. This behavior is absent if the metastasis enters a dormant phase before the threshold for the development of interstitial fluid pressure has been reached. The small size of these metastases maximizes therapeutic success since they consist only of oxygenated cells, and the drug therefore affects all the cells.
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http://dx.doi.org/10.3934/mbe.2020325DOI Listing
September 2020

Breast cancer organoid model allowed to reveal potentially beneficial combinations of 3,3'-diindolylmethane and chemotherapy drugs.

Biochimie 2020 Dec 22;179:217-227. Epub 2020 Oct 22.

Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow, 101000, Russia; P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, 125284, Russia. Electronic address:

Epigenetic alterations represent promising therapeutic targets in cancer treatment. Recently it was revealed that small molecules have the potential to act as microRNA silencers. Capacity to bind the discrete stem-looped structure of pre-miR-21 and prevent its maturation opens opportunities to utilize such compounds for the prevention of initiation, progression, and chemoresistance of cancer. Molecular simulations performed earlier identified 3,3'-diindolylmethane (DIM) as a potent microRNA-21 antagonist. However, data on DIM and microRNA-21 interplay is controversial, which may be caused by the limitations of the cell lines.
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http://dx.doi.org/10.1016/j.biochi.2020.10.007DOI Listing
December 2020

Thioredoxin Interacting Protein (TXNIP) Is Differentially Expressed in Human Tumor Samples but Is Absent in Human Tumor Cell Line Xenografts: Implications for Its Use as an Immunosurveillance Marker.

Cancers (Basel) 2020 Oct 18;12(10). Epub 2020 Oct 18.

Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Thioredoxin interacting protein (TXNIP) is a metabolic protein critically involved in redox homeostasis and has been proposed as a tumor suppressor gene in a variety of malignancies. Accordingly, TXNIP is downregulated in breast, bladder, and gastric cancer and in tumor transplant models TXNIP overexpression inhibits growth and metastasis. As TXNIP protein expression has only been investigated in few malignancies, we employed immunohistochemical detection in a large multi-tumor tissue microarray consisting of 2,824 samples from 94 different tumor entities. In general, TXNIP protein was present only in a small proportion of primary tumor samples and in these cases was differently expressed depending on tumor stage and subtype (e.g., renal cell carcinoma, thyroid cancer, breast cancer, and ductal pancreatic cancer). Further, TXNIP protein expression was determined in primary mouse xenograft tumors derived from human cancer cell lines and was immunohistochemically absent in all xenograft tumors investigated. Intriguingly, TXNIP expression became gradually lower in the proximity of the primary tumor tissue and was absent in leukocytes directly adjacent to tumor tissue. In conclusion, these findings suggest that TXNIP downregulation is as a common feature in human tumor xenograft models and that intra-tumoral leukocytes down-regulate TXNIP. Hence TXNIP expression might be used to monitor the functional state of tumor-infiltrating leukocytes in tissue sections.
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http://dx.doi.org/10.3390/cancers12103028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603212PMC
October 2020

Angiotensin Inhibition, TGF-β and EMT in Cancer.

Cancers (Basel) 2020 Sep 28;12(10). Epub 2020 Sep 28.

Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Angiotensin inhibitors are standard drugs in cardiovascular and renal diseases that have antihypertensive and antifibrotic properties. These drugs also exert their antifibrotic effects in cancer by reducing collagen and hyaluronan deposition in the tumor stroma, thus enhancing drug delivery. Angiotensin II signaling interferes with the secretion of the cytokine TGF-β-a known driver of malignancy. TGF-β stimulates matrix production in cancer-associated fibroblasts, and thus drives desmoplasia. The effect of TGF-β on cancer cells itself is stage-dependent and changes during malignant progression from inhibitory to stimulatory. The intracellular signaling for the TGF-β family can be divided into an SMAD-dependent canonical pathway and an SMAD-independent noncanonical pathway. These capabilities have made TGF-β an interesting target for numerous drug developments. TGF-β is also an inducer of epithelial-mesenchymal transition (EMT). EMT is a highly complex spatiotemporal-limited process controlled by a plethora of factors. EMT is a hallmark of metastatic cancer, and with its reversal, an important step in the metastatic cascade is characterized by a loss of epithelial characteristics and/or the gain of mesenchymal traits.
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http://dx.doi.org/10.3390/cancers12102785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601465PMC
September 2020

Radiosensitisation and enhanced tumour growth delay of colorectal cancer cells by sustained treatment with trifluridine/tipiracil and X-rays.

Cancer Lett 2020 11 4;493:179-188. Epub 2020 Sep 4.

Department of Radiotherapy and Radiation Oncology, University Cancer Center Hamburg - Hubertus Wald Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Trifluridine/tipiracil (FTD/TPI; marketed as Lonsurf®) has shown clinically relevant activity after fluoropyrimidine failure in colorectal cancer and may thus be of increased efficacy compared with current standard capecitabine chemoradiation. Here we investigated the colorectal cancer cell lines HT29, HCT116, SW48 and Caco-2 to provide a preclinical rationale for FTD/TPI-based chemoradiation treatment. All lines incorporated similar amounts of FTD, irrespective of treatment concentration and duration, then arrested in S phase, showed persistent γH2AX induction and eventually underwent endoreplication, resulting in polyploidy. Clonogenic assays performed for four combined treatment schedules demonstrated additivity for treatments given within 6 h of each other. However, 24 h FTD/TPI treatment prior to irradiation caused 1.6-2.4 fold radiosensitisation. Combined in vivo treatment was well tolerated and caused a marked tumour growth delay, similar to capecitabine radiochemotherapy regimes. Prolonged S phase arrest, persistent γH2AX signalling, endoreplication and polyploidy may contribute to the cytotoxicity of FTD/TPI. The strong radiosensitising effect observed in vitro after prolonged treatment with FTD/TPI and equivalence with capecitabine-based chemoradiation in vivo support a daily fractionated combined regime of FTD/TPI and radiation in rectal cancer treatment. This is now being tested in a phase I/II clinical trial (NCT04177602).
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http://dx.doi.org/10.1016/j.canlet.2020.08.038DOI Listing
November 2020

Xenograft-derived mRNA/miR and protein interaction networks of systemic dissemination in human prostate cancer.

Eur J Cancer 2020 09 1;137:93-107. Epub 2020 Aug 1.

Institute of Anatomy and Experimental Morphology, University Medical Center, Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany.

Background: Distant metastasis formation is the major clinical problem in prostate cancer (PCa) and the underlying mechanisms remain poorly understood. Our aim was to identify novel molecules that functionally contribute to human PCa systemic dissemination based on unbiased approaches.

Methods: We compared mRNA, microRNA (miR) and protein expression levels in established human PCa xenograft tumours with high (PC-3), moderate (VCaP) or weak (DU-145) spontaneous micrometastatic potential. By focussing on those mRNAs, miRs and proteins that were differentially regulated among the xenograft groups and known to interact with each other we constructed dissemination-related mRNA/miR and protein/miR networks. Next, we clinically and functionally validated our findings.

Results: Besides known determinants of PCa progression and/or metastasis, our interaction networks include several novel candidates. We observed a clear role of epithelial-to-mesenchymal transition (EMT) pathways for PCa dissemination, which was additionally confirmed by an independent human PCa model (ARCAP-E/-M). Two converging nodes, CD46 (decreasing with metastatic potential) and DDX21 (increasing with metastatic potential), were used to test the clinical relevance of the networks. Intriguingly, both network nodes consistently added prognostic information for patients with PCa whereas CD46 loss predicted poor outcome independent of established parameters. Accordingly, depletion of CD46 in weakly metastatic PCa cells induced EMT-like properties in vitro and spontaneous micrometastasis formation in vivo.

Conclusions: The clinical and functional relevance of the dissemination-related interaction networks shown here could be successfully validated by proof-of-principle experiments. Therefore, we suggest a direct pro-metastatic, clinically relevant role for the multiple novel candidates included in this study; these should be further exploited by future studies.
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http://dx.doi.org/10.1016/j.ejca.2020.06.025DOI Listing
September 2020

Ectopic Expression of Hematopoietic SHIP1 in Human Colorectal Cancer.

Biomedicines 2020 Jul 15;8(7). Epub 2020 Jul 15.

Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Colorectal cancer (CRC) is a heterogeneous disease that results from the accumulation of mutations in colonic mucosa cells. A subclass of CRC is characterized by microsatellite instability, which is thought to occur mainly through inactivation of the DNA mismatch repair genes and . The inositol 5-phosphatase SHIP1 is expressed predominantly in hematopoietic cells. In this study, the expression of SHIP1 in carcinomas and its putative correlation with clinicopathologic parameters, expression of DNA repair genes and microsatellite instability was investigated. By analyzing a multi-tumor tissue microarray, expression of SHIP1 was detected in 48 out of 72 cancer entities analyzed. The expression of SHIP1 protein of 145 kDa was confirmed by Western blot analysis in 7 out of 14 carcinoma cell lines. Analysis of a large colorectal cancer tissue microarray with 1009 specimens revealed SHIP1 expression in 62% of the samples analyzed. SHIP1 expression was inversely correlated with lymph node metastasis, vascular invasion and tumor grade, and it was positively associated with left-sided tumor localization. Interestingly, a strong relationship between the expression of SHIP1 and nuclear and membranous beta-catenin and the DNA repair genes and was observed.
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http://dx.doi.org/10.3390/biomedicines8070215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400281PMC
July 2020

Recent insights into the role of L1CAM in cancer initiation and progression.

Int J Cancer 2020 12 17;147(12):3292-3296. Epub 2020 Jul 17.

Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.

First described as a neuronal cell adhesion molecule, L1CAM was later identified to be present at increased levels in primary tumors and metastases of various types of cancer. Here, we describe the multifaceted roles of L1CAM that are involved in diverse fundamental steps during tumor initiation and progression, as well as in chemoresistance. Recently, Ganesh et al reported that L1CAM identifies metastasis-initiating cells in colorectal carcinoma exhibiting stem-like cell features, increased tumorigenic potential and enhanced chemoresistance. In this review, we highlight recent advances in L1CAM research with particular emphasis on its role in de-differentiation processes and cancer cell stemness supporting the view that L1CAM is a powerful prognostic factor and a suitable target for improved therapy of metastatic and drug-resistant tumors.
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http://dx.doi.org/10.1002/ijc.33177DOI Listing
December 2020

The initial engraftment of tumor cells is critical for the future growth pattern: a mathematical study based on simulations and animal experiments.

BMC Cancer 2020 Jun 5;20(1):524. Epub 2020 Jun 5.

Competence Center Bioinformatics, Institute for Applied Computer Science, University of Applied Sciences Stralsund, Zur Schwedenschanze 15, 18435, Stralsund, Germany.

Background: Xenograft mouse tumor models are used to study mechanisms of tumor growth and metastasis formation and to investigate the efficacy of different therapeutic interventions. After injection the engrafted cells form a local tumor nodule. Following an initial lag period of several days, the size of the tumor is measured periodically throughout the experiment using calipers. This method of determining tumor size is error prone because the measurement is two-dimensional (calipers do not measure tumor depth). Primary tumor growth can be described mathematically by suitable growth functions, the choice of which is not always obvious. Growth parameters provide information on tumor growth and are determined by applying nonlinear curve fitting.

Methods: We used self-generated synthetic data including random measurement errors to research the accuracy of parameter estimation based on caliper measured tumor data. Fit metrics were investigated to identify the most appropriate growth function for a given synthetic dataset. We studied the effects of measuring tumor size at different frequencies on the accuracy and precision of the estimated parameters. For curve fitting with fixed initial tumor volume, we varied this fixed initial volume during the fitting process to investigate the effect on the resulting estimated parameters. We determined the number of surviving engrafted tumor cells after injection using ex vivo bioluminescence imaging, to demonstrate the effect on experiments of incorrect assumptions about the initial tumor volume.

Results: To select a suitable growth function, measurement data from at least 15 animals should be considered. Tumor volume should be measured at least every three days to estimate accurate growth parameters. Daily measurement of the tumor volume is the most accurate way to improve long-term predictability of tumor growth. The initial tumor volume needs to have a fixed value in order to achieve meaningful results. An incorrect value for the initial tumor volume leads to large deviations in the resulting growth parameters.

Conclusions: The actual number of cancer cells engrafting directly after subcutaneous injection is critical for future tumor growth and distinctly influences the parameters for tumor growth determined by curve fitting.
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http://dx.doi.org/10.1186/s12885-020-07015-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275472PMC
June 2020

Detection of doxorubicin, cisplatin and therapeutic antibodies in formalin-fixed paraffin-embedded human cancer cells.

Histochem Cell Biol 2020 May 3;153(5):367-377. Epub 2020 Mar 3.

Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

A major limitation in the pharmacological treatment of clinically detectable primary cancers and their metastases is their limited accessibility to anti-cancer drugs (cytostatics, inhibitory antibodies, small-molecule inhibitors) critically impairing therapeutic efficacies. Investigations on the tissue distribution of such drugs are rare and have only been based on fresh frozen material or methanol-fixed cell culture cells so far. In this paper, we expand the detection of cisplatin-induced DNA adducts and anthracyclines as well as therapeutic antibodies to routinely prepared formalin-fixed, paraffin-embedded sections (FFPE). Using pre-treated cell lines prepared as FFPE samples comparable to tissues from routine analysis, we demonstrate that our method allows for the detection of chemotherapeutics (anthracyclines by autofluorescence, cisplatin by immune detection of DNA adducts) as well as therapeutic antibodies. This methodology thus allows for analyzing archival FFPE tissues, as demonstrated here for the detection of cisplatin, doxorubicin and trastuzumab in FFPE sections of tumor xenografts from drug-treated mice. Analyzing human tumor samples, this will lead to new insights into the tissue penetration of drugs.
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http://dx.doi.org/10.1007/s00418-020-01857-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225197PMC
May 2020

Systematic analysis of the human tumor cell binding to human vs. murine E- and P-selectin under static vs. dynamic conditions.

Glycobiology 2020 08;30(9):695-709

Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.

Endothelial E- and P-selectins promote metastasis formation by interacting with sialyl-Lewis X and A (sLeX/sLeA) on circulating tumor cells. This interaction precedes extravasation and can take place under dynamic and static conditions. Metastasis formation is often studied in xenograft models. However, it is unclear whether species differences exist in the ligand specificity of human (h) vs. murine (m) selectins and whether different ligands are functional under dynamic vs. static conditions. We systematically compared the h vs. m E- and P-selectin (ESel/PSel) binding of a range of human tumor cells under dynamic vs. static conditions. The tumor cells were categorized by their sLeA/X status (sLeA+/sLeX+, sLeA-/sLeX+ and sLeA-/sLeX-). The general biological nature of the tumor-selectin interaction was analyzed by applying several tumor cell treatments (anti-sLeA/X blockade, neuraminidase, pronase and inhibition of O/N-glycosylation). We observed remarkable differences in the static vs. dynamic interaction of tumor cells with h vs. m ESel/PSel depending on their sLeA/X status. The tumor cell treatments mostly affected either static or dynamic as well as either h- or m-selectin interaction. mESel showed a higher diversity of potential ligands than hESel. Inhibition of O-GalNAc-glycosylation also affected glycosphingolipid synthesis. Summarized, different ligands on human tumor cells are functional under static vs. dynamic conditions and for the interaction with human vs. murine ESel/PSel. Non-canonical selectin ligands lacking the sLeA/X glycan epitopes exist on human tumor cells. These findings have important implications for the current development of glycomimetic, antimetastatic drugs and encourage the development of immunodeficient mice with humanized selectins.
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http://dx.doi.org/10.1093/glycob/cwaa019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443332PMC
August 2020

Modeling Spontaneous Bone Metastasis Formation of Solid Human Tumor Xenografts in Mice.

Cancers (Basel) 2020 Feb 7;12(2). Epub 2020 Feb 7.

Institute of Anatomy and Experimental Morphology, University Cancer Center Hamburg, 20251 Hamburg, Germany.

The majority of cancer-related deaths are due to hematogenous metastases, and the bone marrow (BM) represents one of the most frequent metastatic sites. To study BM metastasis formation in vivo, the most efficient approach is based on intracardiac injection of human tumor cells into immunodeficient mice. However, such a procedure circumvents the early steps of the metastatic cascade. Here we describe the development of xenograft mouse models (balb/c and severe combined immunodeficient (SCID)), in which BM metastases are spontaneously derived from subcutaneous (s.c.) primary tumors (PTs). As verified by histology, the described methodology including ex vivo bioluminescence imaging (BLI) even enabled the detection of micrometastases in the BM. Furthermore, we established sublines from xenograft primary tumors (PTs) and corresponding BM (BM) metastases using LAN-1 neuroblastoma xenografts as a first example. In vitro "metastasis" assays (viability, proliferation, transmigration, invasion, colony formation) partially indicated pro-metastatic features of the LAN-1-BM compared to the LAN-1-PT subline. Unexpectedly, after s.c. re-injection into mice, LAN-1-BM xenografts developed spontaneous BM metastases less frequently than LAN-1-PT xenografts. This study provides a novel methodologic approach for modelling the spontaneous metastatic cascade of human BM metastasis formation in mice. Moreover, our data indicate that putative bone-metastatic features get rapidly lost upon routine cell culture.
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http://dx.doi.org/10.3390/cancers12020385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072706PMC
February 2020

Electrical Impedance Spectroscopy for Characterization of Prostate PC-3 and DU 145 Cancer Cells.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:6485-6489

The impedance profile of the human PC-3 and DU 145 prostate cancer cells were recorded and compared using Electrical Impedance Spectroscopy. Cells were measured in a special chamber using a four terminal setup to avoid parasitic effects of electrode polarization in low frequencies. Our results show that the two cancer cell lines are readily distinguishable by their impedance spectrum. As PC-3 cells have been shown to be spontaneously metastatic in previous xenograft experiments while DU 145 cells were non-metastatic, Electrical Impedance Spectroscopy has the potential to be developed into a simple diagnostic tool to distinguish metastatic from non-metastatic cells.
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http://dx.doi.org/10.1109/EMBC.2019.8856627DOI Listing
July 2019

Targeting tumor interstitial fluid pressure: will it yield novel successful therapies for solid tumors?

Expert Opin Ther Targets 2019 12 11;23(12):1005-1014. Epub 2019 Dec 11.

Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

: Elevated tumor interstitial fluid pressure (TIFP) is a major barrier to successful cancer treatment. It is mainly caused by an inadequate tumor perfusion resulting from missing lymphatic vessels, a leaky and immature tumor vasculature, an overly stimulated angiogenesis, and interstitial fibrosis. TIFP hampers convection-driven fluid transport within tumors and causes inefficient penetration and distribution of anti-neoplastic drugs.: This review covers mechanisms and regulation of TIFP and gives an overview of strategies to overcome this barrier.: Increased TIFP occurs and hence may be overlooked in molecular biology-driven cancer research. Its pervasiveness means that it can reduce the effectiveness of anti-neoplastic drugs. This is often misinterpreted as drug resistance; it precedes all drug resistance mechanisms operating at the cell level. The key challenge in the field of cancer therapeutics is to find ways to lower TIFP. Several drug therapies have been tried but none of them have had an impact in the clinic. This is an overarching problem in the field of cancer research.
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http://dx.doi.org/10.1080/14728222.2019.1702974DOI Listing
December 2019

-Regulating miR-4274 and Its Host Gene Play a Role in -Dependent Effects on Phenotype of Basal-Like Breast Cancer.

Front Mol Biosci 2019 8;6:122. Epub 2019 Nov 8.

Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow, Russia.

Specificity of RNAi to selected target is challenged by off-target effects, both canonical and non-canonical. Notably, more than half of all human microRNAs are co-expressed with hosting them proteincoding genes. Here we dissect regulatory subnetwork centered on gene, which is associated with low proliferative state and high migratory activity of basal-like breast cancer. We inhibited expression of gene in a model cell line for basal-like breast carcinoma MDA-MB-231, then traced secondary and tertiary effects of this knockdown to , a laminin encoding gene that contributes to the phenotype of triple-negative breast cancer. -regulating miRNA miR-4274 and its host gene were highlighted as intermediate regulators of the expression levels of , which correlated in a basal-like breast carcinoma sample subset of TCGA to the levels of negatively. Overall, our study points that the secondary and tertiary layers of regulatory interactions are certainly underappreciated. As these types of molecular event may significantly contribute to the formation of the cell phenotypes after RNA interference based knockdowns, further studies of multilayered molecular networks affected by RNAi are warranted.
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http://dx.doi.org/10.3389/fmolb.2019.00122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857517PMC
November 2019
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