Publications by authors named "Peter Altevogt"

143 Publications

Reduced Placental CD24 in Preterm Preeclampsia Is an Indicator for a Failure of Immune Tolerance.

Int J Mol Sci 2021 Jul 28;22(15). Epub 2021 Jul 28.

Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6/II, 8010 Graz, Austria.

Introduction: CD24 is a mucin-like glycoprotein expressed at the surface of hematopoietic and tumor cells and was recently shown to be expressed in the first trimester placenta. As it was postulated as an immune suppressor, CD24 may contribute to maternal immune tolerance to the growing fetus. Preeclampsia (PE), a major pregnancy complication, is linked to reduced immune tolerance. Here, we explored the expression of CD24 in PE placenta in preterm and term cases.

Methods: Placentas were derived from first and early second trimester social terminations (N = 43), and third trimester normal term delivery (N = 67), preterm PE (N = 18), and preterm delivery (PTD) (N = 6). CD24 expression was determined by quantitative polymerase chain reaction (qPCR) and Western blotting. A smaller cohort included 3-5 subjects each of term and early PE, and term and preterm delivery controls analyzed by immunohistochemistry.

Results: A higher expression (2.27-fold) of CD24 mRNA was determined in the normal term delivery compared to first and early second trimester cases. The mRNA of preterm PE cases was only higher by 1.31-fold compared to first and early second trimester, while in the age-matched PTD group had a fold increase of 5.72, four times higher compared to preterm PE. The delta cycle threshold (ΔCt) of CD24 mRNA expression in the preterm PE group was inversely correlated with gestational age (r = 0.737) and fetal size (r = 0.623), while correlation of any other group with these parameters was negligible. Western blot analysis revealed that the presence of CD24 protein in placental lysate of preterm PE was significantly reduced compared to term delivery controls ( = 0.026). In immunohistochemistry, there was a reduction of CD24 staining in villous trophoblast in preterm PE cases compared to gestational age-matched PTD cases ( = 0.042). Staining of PE cases at term was approximately twice higher compared to preterm PE cases ( = 0.025) but not different from normal term delivery controls.

Conclusion: While higher CD24 mRNA expression levels were determined for normal term delivery compared to earlier pregnancy stages, this expression level was found to be lower in preterm PE cases, and could be said to be linked to reduced immune tolerance in preeclampsia.
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http://dx.doi.org/10.3390/ijms22158045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348750PMC
July 2021

The signal transducer CD24 suppresses the germ cell program and promotes an ectodermal rather than mesodermal cell fate in embryonal carcinomas.

Mol Oncol 2021 Jul 22. Epub 2021 Jul 22.

Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany.

Testicular germ cell tumors (GCTs) are stratified into seminomas and nonseminomas. Seminomas share many histological and molecular features with primordial germ cells, whereas the nonseminoma stem cell population-embryonal carcinoma (EC)-is pluripotent and thus able to differentiate into cells of all three germ layers (teratomas). Furthermore, ECs are capable of differentiating into extra-embryonic lineages (yolk sac tumors, choriocarcinomas). In this study, we deciphered the molecular and (epi)genetic mechanisms regulating expression of CD24, a highly glycosylated signaling molecule upregulated in many cancers. CD24 is overexpressed in ECs compared with other GCT entities and can be associated with an undifferentiated pluripotent cell fate. We demonstrate that CD24 can be transactivated by the pluripotency factor SOX2, which binds in proximity to the CD24 promoter. In GCTs, CD24 expression is controlled by epigenetic mechanisms, that is, histone acetylation, since CD24 can be induced by the application histone deacetylase inhibitors. Vice versa, CD24 expression is downregulated upon inhibition of histone methyltransferases, E3 ubiquitin ligases, or bromodomain (BRD) proteins. Additionally, three-dimensional (3D) co-cultivation of EC cells with microenvironmental cells, such as fibroblasts, and endothelial or immune cells, reduced CD24 expression, suggesting that crosstalk with the somatic microenvironment influences CD24 expression. In a CRISPR/Cas9 deficiency model, we demonstrate that CD24 fulfills a bivalent role in differentiation via regulation of homeobox, and phospho- and glycoproteins; that is, it is involved in suppressing the germ cell/spermatogenesis program and mesodermal/endodermal differentiation, while poising the cells for ectodermal differentiation. Finally, blocking CD24 by a monoclonal antibody enhanced sensitivity toward cisplatin in EC cells, including cisplatin-resistant subclones, highlighting CD24 as a putative target in combination with cisplatin.
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http://dx.doi.org/10.1002/1878-0261.13066DOI Listing
July 2021

Tumor promoting capacity of polymorphonuclear myeloid-derived suppressor cells and their neutralization.

Int J Cancer 2021 Nov 17;149(9):1628-1638. Epub 2021 Jul 17.

Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Myeloid-derived suppressor cells (MDSC) represent a highly immunosuppressive population that expands in tumor bearing hosts and inhibits both T and NK cell antitumor effector functions. Among MDSC subpopulations, the polymorphonuclear (PMN) one is gaining increasing interest since it is a predominant MDSC subset in most cancer entities and inherits unique properties to facilitate metastatic spread. In addition, further improvement in distinguishing PMN-MDSC from neutrophils has contributed to the design of novel therapeutic approaches. In this review, we summarize the current view on the origin of PMN-MDSC and their relation to classical neutrophils. Furthermore, we outline the metastasis promoting features of these cells and promising strategies of their targeting to improve the efficacy of cancer immunotherapy.
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http://dx.doi.org/10.1002/ijc.33731DOI Listing
November 2021

Repression Leads to Enhanced NOTCH Signaling in Fusion Positive Prostate Cancer Cells.

Cancers (Basel) 2021 Feb 25;13(5). Epub 2021 Feb 25.

Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany.

About 50% of prostate cancer (PCa) tumors are (T2E) fusion-positive (T2E+), but the role of T2E in PCa progression is not fully understood. We were interested in investigating epigenomic alterations associated with T2E+ PCa. Using different sequencing cohorts, we found several transcripts of the cluster to be repressed in T2E+ PCa. This repression correlated strongly with enhanced expression of NOTCH and several of its target genes in TCGA and ICGC PCa RNA-seq data. We corroborated these findings using a cellular model with inducible T2E expression. Overexpression of in vitro led to silencing of genes associated with NOTCH signaling (, ) and . Interestingly, overexpression led to the repression of , a negative regulator of the transcription factor , the primary effector of NOTCH signaling, and promoted cell proliferation by repressing the cell cycle inhibitor p21. Inhibition of NOTCH as well as knockdown of reduced the oncogenic properties of PCa cell lines. Using tissue microarray analysis encompassing 533 human PCa cores, ERG-positive areas exhibited significantly increased expression. Taken together, our data suggest that an epigenomic regulatory network enhances NOTCH signaling and thereby contributes to the oncogenic properties of T2E+ PCa.
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http://dx.doi.org/10.3390/cancers13050964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975324PMC
February 2021

Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression.

Cancers (Basel) 2021 Feb 10;13(4). Epub 2021 Feb 10.

Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression.

Methods: Using the transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas.

Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells.

Conclusions: We provide evidence for the tumorpromoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.
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http://dx.doi.org/10.3390/cancers13040726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916588PMC
February 2021

DNA Promoter Methylation and ERG Regulate the Expression of CD24 in Prostate Cancer.

Am J Pathol 2021 04 22;191(4):618-630. Epub 2021 Jan 22.

Institute of Pathology, Center for Integrated Oncology, University of Bonn, Bonn, Germany; Center for Integrated Oncology Aachen/Bonn/Cologne/Dusseldorf, Bonn, Germany. Electronic address:

CD24 is overexpressed in many human cancers and is a driver of tumor progression. Herein, molecular mechanisms leading to up-regulation of CD24 in prostate cancer were studied. DNA methylation of the CD24 gene promoter at four loci using quantitative methylation-specific PCR was evaluated. Expression of CD24 in tumor tissues was studied by immunohistochemistry. To corroborate the results in vitro, ERG-inducible LNCaP TMPRSS2:ERG (T2E) cells and luciferase promoter assays were used. DNA methylation of the CD24 promoter was significantly higher in tumors than in benign tissue and was associated with biochemical recurrence-free survival, tumor grade, and stage. CD24 mRNA and protein expression were significantly higher in T2E-positive, ERG-overexpressing, and/or PTEN-deficient cases. Higher levels of CD24 protein expression conferred shorter biochemical recurrence-free survival, and these observations were confirmed using The Cancer Genome Atlas prostate adenocarcinoma data. In silico analysis of the CD24 promoter revealed an ERG binding site in between the DNA methylation sites. ERG overexpression led to a strong induction of CD24 mRNA and protein expression. Luciferase promoter assays using the wild-type and mutated ERG binding site within the CD24 promoter showed ERG-dependent activation. Collectively, our results suggest that promoter DNA methylation of the CD24 gene and T2E fusion status are factors involved in the up-regulation of CD24 in patients with prostate cancer.
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http://dx.doi.org/10.1016/j.ajpath.2020.12.014DOI Listing
April 2021

HER3-Receptor-Mediated STAT3 Activation Plays a Central Role in Adaptive Resistance toward Vemurafenib in Melanoma.

Cancers (Basel) 2020 Dec 14;12(12). Epub 2020 Dec 14.

Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Melanoma is an aggressive form of skin cancer that is often characterized by activating mutations in the Mitogen-Activated Protein (MAP) kinase pathway, causing hyperproliferation of the cancer cells. Thus, inhibitors targeting this pathway were developed. These inhibitors are initially very effective, but the occurrence of resistance eventually leads to a failure of the therapy and is the major obstacle for clinical success. Therefore, investigating the mechanisms causing resistance and discovering ways to overcome them is essential for the success of therapy. Here, we observed that treatment of melanoma cells with the B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) inhibitor vemurafenib caused an increased cell surface expression and activation of human epidermal growth factor receptor 3 (HER3) by shed ligands. HER3 promoted the activation of signal transducer and activator of transcription 3 (STAT3) resulting in upregulation of the STAT3 target gene SRY-Box Transcription Factor 2 () and survival of the cancer cells. Pharmacological blocking of HER led to a diminished STAT3 activation and increased sensitivity toward vemurafenib. Moreover, HER blocking sensitized vemurafenib-resistant cells to drug treatment. We conclude that the inhibition of the STAT3 upstream regulator HER might help to overcome melanoma therapy resistance toward targeted therapies.
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http://dx.doi.org/10.3390/cancers12123761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764938PMC
December 2020

IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy.

Cell Immunol 2021 01 29;359:104254. Epub 2020 Nov 29.

Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. Electronic address:

Myeloid-derived suppressor cells (MDSC) are generated during tumor progression and suppress the anti-tumor functions of T and natural killer (NK) cells. Their enrichment is associated with a bad prognosis and a worse outcome of immunotherapy in cancer patients. The cytokine interleukin (IL)-6 was found to be a crucial regulator of MDSC accumulation and activation as well as a factor, stimulating tumor cell proliferation, survival, invasiveness and metastasis. Accordingly, IL-6 can serve as a negative prognostic marker in cancer. On the other hand, this cytokine is also involved in T cell activation. This review discusses the pleiotropic effects of IL-6 on immune cell populations that are critical for tumor development, such as MDSC and T cells, and summarizes the data on targeting IL-6 or IL-6 receptor (IL-6R) for tumor immunotherapy to block MDSC-mediated immunosuppression in cancer patients.
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http://dx.doi.org/10.1016/j.cellimm.2020.104254DOI Listing
January 2021

Myeloid Cell Modulation by Tumor-Derived Extracellular Vesicles.

Int J Mol Sci 2020 Aug 31;21(17). Epub 2020 Aug 31.

Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Extracellular vesicles (EV) can carry proteins, RNA and DNA, thus serving as communication tools between cells. Tumor cells secrete EV, which can be taken up by surrounding cells in the tumor microenvironment as well as by cells in distant organs. Tumor-derived EV (TEV) contain factors induced by tumor-associated hypoxia such as heat shock proteins or a variety of microRNA (miRNA). The interaction of TEV with tumor and host cells can promote cancer angiogenesis, invasion and metastasis. Myeloid cells are widely presented in tissues, comprise the majority of immune cells and play an essential role in immune reactions and tissue remodeling. However, in cancer, the differentiation of myeloid cells and their functions are impaired, resulting in tumor promotion. Such alterations are due to chronic inflammatory conditions associated with cancer and are mediated by the tumor secretome, including TEV. A high capacity of myeloid cells to clear EV from circulation put them in the central position in EV-mediated formation of pre-metastatic niches. The exposure of myeloid cells to TEV could trigger numerous signaling pathways. Progenitors of myeloid cells alter their differentiation upon the contact with TEV, resulting in the generation of myeloid-derived suppressor cells (MDSC), inhibiting anti-tumor function of T and natural killer (NK) cells and promoting thereby tumor progression. Furthermore, TEV can augment MDSC immunosuppressive capacity. Different subsets of mature myeloid cells such as monocytes, macrophages, dendritic cells (DC) and granulocytes take up TEV and acquire a protumorigenic phenotype. However, the delivery of tumor antigens to DC by TEV was shown to enhance their immunostimulatory capacity. The present review will discuss a diverse and complex EV-mediated crosstalk between tumor and myeloid cells in the context of the tumor type, TEV-associated cargo molecules and type of recipient cells.
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http://dx.doi.org/10.3390/ijms21176319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504548PMC
August 2020

Novel insights into the function of CD24: A driving force in cancer.

Int J Cancer 2021 02 3;148(3):546-559. Epub 2020 Sep 3.

Institute of Pathology, University of Bonn, Bonn, Germany.

CD24 is a highly glycosylated protein with a small protein core that is linked to the plasma membrane via a glycosyl-phosphatidylinositol anchor. CD24 is primarily expressed by immune cells but is often overexpressed in human tumors. In cancer, CD24 is a regulator of cell migration, invasion and proliferation. Its expression is associated with poor prognosis and it is used as cancer stemness marker. Recently, CD24 on tumor cells was identified as a phagocytic inhibitor ("do not eat me" signal) having a suppressive role in tumor immunity via binding to Siglec-10 on macrophages. This finding is reminiscent of the demonstration that soluble CD24-Fc can dampen the immune system in autoimmune disease. In the present review, we summarize recent progress on the role of the CD24-Siglec-10 binding axis at the interface between tumor cells and the immune system, and the role of CD24 genetic polymorphisms in cancer. We describe the specific function of cytoplasmic CD24 and discuss the presence of CD24 on tumor-released extracellular vesicles. Finally, we evaluate the potential of CD24-based immunotherapy.
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http://dx.doi.org/10.1002/ijc.33249DOI Listing
February 2021

IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma.

J Immunother Cancer 2020 08;8(2)

Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center, Mannheim, Baden-Württemberg, Germany

Background: Myeloid-derived suppressor cells (MDSC) play a major role in the immunosuppressive melanoma microenvironment. They are generated under chronic inflammatory conditions characterized by the constant production of inflammatory cytokines, chemokines and growth factors, including IL-6. Recruitment of MDSC to the tumor is mediated by the interaction between chemokines and chemokine receptors, in particular C-C chemokine receptor (CCR)5. Here, we studied the mechanisms of CCR5 upregulation and increased immunosuppressive function of CCR5 MDSC.

Methods: The immortalized myeloid suppressor cell line MSC-2, primary immature myeloid cells and in vitro differentiated MDSC were used to determine factors and molecular mechanisms regulating CCR5 expression and immunosuppressive markers at the mRNA and protein levels. The relevance of the identified pathways was validated on the transgenic mouse melanoma model, which was also used to target the identified pathways in vivo.

Results: IL-6 upregulated the expression of CCR5 and arginase 1 in MDSC by a STAT3-dependent mechanism. MDSC differentiated in the presence of IL-6 strongly inhibited CD8 T cell functions compared with MDSC differentiated without IL-6. A correlation between IL-6 levels, phosphorylated STAT3 and CCR5 expression in tumor-infiltrating MDSC was demonstrated in the transgenic melanoma mouse model. Surprisingly, IL-6 overexpressing tumors grew significantly slower in mice accompanied by CD8 T cell activation. Moreover, transgenic melanoma-bearing mice treated with IL-6 blocking antibodies showed significantly accelerated tumor development.

Conclusion: Our in vitro and ex vivo findings demonstrated that IL-6 induced CCR5 expression and a strong immunosuppressive activity of MDSC, highlighting this cytokine as a promising target for melanoma immunotherapy. However, IL-6 blocking therapy did not prove to be effective in transgenic melanoma-bearing mice but rather aggravated tumor progression. Further studies are needed to identify particular combination therapies, cancer entities or patient subsets to benefit from the anti-IL-6 treatment.
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http://dx.doi.org/10.1136/jitc-2020-000949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422659PMC
August 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

Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma.

Int J Mol Sci 2020 Mar 30;21(7). Epub 2020 Mar 30.

Clinical Cooperation Unit Dermato-Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Although melanoma is one of the most immunogenic tumors, it has an ability to evade anti-tumor immune responses by exploiting tolerance mechanisms, including negative immune checkpoint molecules. The most extensively studied checkpoints represent cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Immune checkpoint inhibitors (ICI), which were broadly applied for melanoma treatment in the past decade, can unleash anti-tumor immune responses and result in melanoma regression. Patients responding to the ICI treatment showed long-lasting remission or disease control status. However, a large group of patients failed to respond to this therapy, indicating the development of resistance mechanisms. Among them are intrinsic tumor properties, the dysfunction of effector cells, and the generation of immunosuppressive tumor microenvironment (TME). This review discusses achievements of ICI treatment in melanoma, reasons for its failure, and promising approaches for overcoming the resistance. These methods include combinations of different ICI with each other, strategies for neutralizing the immunosuppressive TME and combining ICI with other anti-cancer therapies such as radiation, oncolytic viral, or targeted therapy. New therapeutic approaches targeting other immune checkpoint molecules are also discussed.
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http://dx.doi.org/10.3390/ijms21072367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178114PMC
March 2020

SOX2 in development and cancer biology.

Semin Cancer Biol 2020 12 11;67(Pt 1):74-82. Epub 2019 Aug 11.

Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. Electronic address:

The transcription factor SOX2 is essential for embryonic development and plays a crucial role in maintaining the stemness of embryonic cells and various adult stem cell populations. On the other hand, dysregulation of SOX2 expression is associated with a multitude of cancer types and it has been shown that SOX2 positively affects cancer cell traits such as the capacity to proliferate, migrate, invade and metastasize. Moreover, there is growing evidence that SOX2 mediates resistance towards established cancer therapies and that it is expressed in cancer stem cells. These findings indicate that studying the role of SOX2 in the context of cancer progression could lead to the development of new therapeutic options. In this review, the current knowledge about the role of SOX2 in development, maintenance of stemness, cancer progression and the resistance towards cancer therapies is summarized.
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http://dx.doi.org/10.1016/j.semcancer.2019.08.007DOI Listing
December 2020

Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma.

J Natl Cancer Inst 2020 05;112(5):507-515

Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA.

Background: Treatment failures in cancers, including multiple myeloma (MM), are most likely due to the persistence of a minor population of tumor-initiating cells (TICs), which are noncycling or slowly cycling and very drug resistant.

Methods: Gene expression profiling and real-time quantitative reverse transcription polymerase chain reaction were employed to define genes differentially expressed between the side-population cells, which contain the TICs, and the main population of MM cells derived from 11 MM patient samples. Self-renewal potential was analyzed by clonogenicity and drug resistance of CD24+ MM cells. Flow cytometry (n = 60) and immunofluorescence (n = 66) were applied on MM patient samples to determine CD24 expression. Therapeutic effects of CD24 antibodies were tested in xenograft MM mouse models containing three to six mice per group.

Results: CD24 was highly expressed in the side-population cells, and CD24+ MM cells exhibited high expression of induced pluripotent or embryonic stem cell genes. CD24+ MM cells showed increased clonogenicity, drug resistance, and tumorigenicity. Only 10 CD24+ MM cells were required to develop plasmacytomas in mice (n = three of five mice after 27 days). The frequency of CD24+ MM cells was highly variable in primary MM samples, but the average of CD24+ MM cells was 8.3% after chemotherapy and in complete-remission MM samples with persistent minimal residual disease compared with 1.0% CD24+ MM cells in newly diagnosed MM samples (n = 26). MM patients with a high initial percentage of CD24+ MM cells had inferior progression-free survival (hazard ratio [HR] = 3.81, 95% confidence interval [CI] = 5.66 to 18.34, P < .001) and overall survival (HR = 3.87, 95% CI = 16.61 to 34.39, P = .002). A CD24 antibody inhibited MM cell growth and prevented tumor progression in vivo.

Conclusion: Our studies demonstrate that CD24+ MM cells maintain the TIC features of self-renewal and drug resistance and provide a target for myeloma therapy.
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http://dx.doi.org/10.1093/jnci/djz159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225664PMC
May 2020

Melanoma Extracellular Vesicles Generate Immunosuppressive Myeloid Cells by Upregulating PD-L1 via TLR4 Signaling.

Cancer Res 2019 Sep 23;79(18):4715-4728. Epub 2019 Jul 23.

Clinical Cooperation Unit Dermato-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Tumor cell-derived extracellular vesicles (EV) convert normal myeloid cells into myeloid-derived suppressor cells (MDSC), inhibiting antitumor immune responses. Here, we show that EV from Ret mouse melanoma cells upregulate the expression of programmed cell death ligand 1 (PD-L1) on mouse immature myeloid cells (IMC), leading to suppression of T-cell activation. PD-L1 expression and the immunosuppressive potential of EV-generated MDSC were dependent on the expression of Toll-like receptors (TLR). IMC from Tlr4 mice failed to increase T-cell PD-L1 expression and immunosuppression with Ret-EV treatment, and this effect was dependent on heat-shock protein 86 (HSP86) as HSP86-deficient Ret cells could not stimulate PD-L1 expression on normal IMC; IMC from Tlr2 and Tlr7 mice demonstrated similar results, although to a lesser extent. HSP86-deficient Ret cells slowed tumor progression associated with decreased frequency of tumor-infiltrating PD-L1CD11bGr1 MDSC. EV from human melanoma cells upregulated PD-L1 and immunosuppression of normal monocytes dependent on HSP86. These findings highlight a novel EV-mediated mechanism of MDSC generation from normal myeloid cells, suggesting the importance of EV targeting for tumor therapy. SIGNIFICANCE: These findings validate the importance of TLR4 signaling in reprogramming normal myeloid cells into functional myeloid-derived suppressor cells.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0053DOI Listing
September 2019

Role of STAT3 dependent SOX2 and CD24 expression in melanoma cell adaptive resistance towards targeted therapies.

Oncotarget 2019 Mar 1;10(18):1662-1663. Epub 2019 Mar 1.

Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.

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http://dx.doi.org/10.18632/oncotarget.26718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422197PMC
March 2019

Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression.

Br J Cancer 2019 01 9;120(1):16-25. Epub 2018 Nov 9.

Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Under steady-state conditions, bone marrow-derived immature myeloid cells (IMC) differentiate into granulocytes, macrophages and dendritic cells (DCs). This differentiation is impaired under chronic inflammatory conditions, which are typical for tumour progression, leading to the accumulation of IMCs. These cells are capable of inducing strong immunosuppressive effects through the expression of various cytokines and immune regulatory molecules, inhibition of lymphocyte homing, stimulation of other immunosuppressive cells, depletion of metabolites critical for T cell functions, expression of ectoenzymes regulating adenosine metabolism, and the production of reactive species. IMCs are therefore designated as myeloid-derived suppressor cells (MDSCs), and have been shown to accumulate in tumour-bearing mice and cancer patients. MDSCs are considered to be a strong contributor to the immunosuppressive tumour microenvironment and thus an obstacle for many cancer immunotherapies. Consequently, numerous studies are focused on the characterisation of MDSC origin and their relationship to other myeloid cell populations, their immunosuppressive capacity, and possible ways to inhibit MDSC function with different approaches being evaluated in clinical trials. This review analyses the current state of knowledge on the origin and function of MDSCs in cancer, with a special emphasis on the immunosuppressive pathways pursued by MDSCs to inhibit T cell functions, resulting in tumour progression. In addition, we describe therapeutic strategies and clinical benefits of MDSC targeting in cancer.
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http://dx.doi.org/10.1038/s41416-018-0333-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325125PMC
January 2019

Correction to: Epigenetic regulation of L1CAM in endometrial carcinoma: comparison to cancer-testis (CT-X) antigens.

BMC Cancer 2018 10 29;18(1):1047. Epub 2018 Oct 29.

Department of Translational Immunology, German Cancer Research Center, D015, D 69120, Heidelberg, Germany.

Following publication of the original article [1], we have been alerted to errors in Figs. 2 and 8. In Fig. 2B, the GAPDH loading control for Hec1A cells is shown twice in error (in Fig. 2B and Fig. 2C). In Fig. 8, in testis case 1 (first column) the MAGE-A4 staining panel was repeated and also appears as the NY-ESO-1 staining panel in error. The corrected versions of Fig. 2 and Fig. 8 are shown below. We apologize for this inconvenience.
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http://dx.doi.org/10.1186/s12885-018-4928-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205797PMC
October 2018

Targeting SOX2 in anticancer therapy.

Expert Opin Ther Targets 2018 12 26;22(12):983-991. Epub 2018 Oct 26.

a Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology , University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg , Mannheim , Germany.

Introduction: SOX2 is a transcription factor that is important in the development and maintenance of the stem cell state. Furthermore, SOX2 is associated with cancer progression because it promotes the migration, invasion, and proliferation of cancer cells. SOX2 is also expressed in cancer stem cells and appears to be involved in the resistance toward anticancer therapies. These features render SOX2 an attractive target for cancer therapy. Areas covered: In this review, we highlight the role of SOX2 in cancer and in the resistance toward anticancer therapies. We summarize recent studies dealing with SOX2 as a direct or indirect therapeutic target in cancer. Expert opinion: SOX2 is an attractive target in cancer therapy because of its role in cancer progression and therapy resistance. SOX2 is a transcription factor, hence direct targeting is difficult. Studies aimed at a functional depletion, for example by knock-down with siRNAs, are difficult to translate into clinical settings. Alternatively, the identification of SOX2 upstream or downstream regulators that are easier to target is of paramount importance.
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http://dx.doi.org/10.1080/14728222.2018.1538359DOI Listing
December 2018

Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma.

J Clin Invest 2018 12 5;128(12):5505-5516. Epub 2018 Nov 5.

Unit of Immunotherapy of Human Tumors, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano, Milan, Italy.

The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs were increased in circulating CD14+ monocytes, plasma, and tumor samples, where they correlated with the myeloid cell infiltrate. In plasma, their baseline levels clustered with the clinical efficacy of CTLA-4 or programmed cell death protein 1 (PD-1) blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.
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http://dx.doi.org/10.1172/JCI98060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264733PMC
December 2018

Myeloid-Derived Suppressor Cells Hinder the Anti-Cancer Activity of Immune Checkpoint Inhibitors.

Front Immunol 2018 11;9:1310. Epub 2018 Jun 11.

Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Immune checkpoint inhibitors (ICI) used for cancer immunotherapy were shown to boost the existing anti-tumor immune response by preventing the inhibition of T cells by tumor cells. Antibodies targeting two negative immune checkpoint pathways, namely cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death-ligand 1 (PD-L1), have been approved first for patients with melanoma, squamous non-small cell lung cancer (NSCLC), and renal cell carcinoma. Clinical trials are ongoing to verify the efficiency of these antibodies for other cancer types and to evaluate strategies to block other checkpoint molecules. However, a number of patients do not respond to this treatment possibly due to profound immunosuppression, which is mediated partly by myeloid-derived suppressor cells (MDSC). This heterogeneous population of immature myeloid cells can strongly inhibit anti-tumor activities of T and NK cells and stimulate regulatory T cells (Treg), leading to tumor progression. Moreover, MDSC can contribute to patient resistance to immune checkpoint inhibition. Accumulating evidence demonstrates that the frequency and immunosuppressive function of MDSC in cancer patients can be used as a predictive marker for therapy response. This review focuses on the role of MDSC in immune checkpoint inhibition and provides an analysis of combination strategies for MDSC targeting together with ICI to improve their therapeutic efficiency in cancer patients.
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http://dx.doi.org/10.3389/fimmu.2018.01310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004385PMC
June 2018

SOX2-mediated upregulation of CD24 promotes adaptive resistance toward targeted therapy in melanoma.

Int J Cancer 2018 12 16;143(12):3131-3142. Epub 2018 Oct 16.

Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, D-68135, Germany.

Melanoma is often characterized by a constitutively active RAS-RAF-MEK-ERK pathway. For targeted therapy, BRAF inhibitors are available that are powerful in the beginning but resistance occurs rather fast. A better understanding of the mechanisms of resistance is urgently needed to increase the success of the treatment. Here, we observed that SOX2 and CD24 are upregulated upon BRAF inhibitor treatment. A similar upregulation was seen in targeted therapy-resistant, melanoma-derived induced pluripotent cancer cells (iPCCs). SOX2 and CD24 are known to promote an undifferentiated and cancer stem cell-like phenotype associated with resistance. We, therefore, elucidated the role of SOX2 and CD24 in targeted therapy resistance in more detail. We found that the upregulation of SOX2 and CD24 required activation of STAT3 and that SOX2 induced the expression of CD24 by binding to its promoter. We find that the overexpression of SOX2 or CD24 significantly increases the resistance toward BRAF inhibitors, while SOX2 knock-down rendered cells more sensitivity toward treatment. The overexpression of CD24 or SOX2 induced Src and STAT3 activity. Importantly, by either CD24 knock-down or Src/STAT3 inhibition in resistant SOX2-overexpressing cells, the sensitivity toward BRAF inhibitors was re-established. Hence, we suggest a novel mechanism of adaptive resistance whereby BRAF inhibition is circumvented via the activation of STAT3, SOX2 and CD24. Thus, to prevent adaptive resistance, it might be beneficial to combine Src/STAT3 inhibitors together with MAPK pathway inhibitors.
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http://dx.doi.org/10.1002/ijc.31609DOI Listing
December 2018

Targeting Myeloid-Derived Suppressor Cells to Bypass Tumor-Induced Immunosuppression.

Front Immunol 2018 2;9:398. Epub 2018 Mar 2.

Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.

The immune system has many sophisticated mechanisms to balance an extensive immune response. Distinct immunosuppressive cells could protect from excessive tissue damage and autoimmune disorders. Tumor cells take an advantage of those immunosuppressive mechanisms and establish a strongly immunosuppressive tumor microenvironment (TME), which inhibits antitumor immune responses, supporting the disease progression. Myeloid-derived suppressor cells (MDSC) play a crucial role in this immunosuppressive TME. Those cells represent a heterogeneous population of immature myeloid cells with a strong immunosuppressive potential. They inhibit an antitumor reactivity of T cells and NK cells. Furthermore, they promote angiogenesis, establish pre-metastatic niches, and recruit other immunosuppressive cells such as regulatory T cells. Accumulating evidences demonstrated that the enrichment and activation of MDSC correlated with tumor progression, recurrence, and negative clinical outcome. In the last few years, various preclinical studies and clinical trials targeting MDSC showed promising results. In this review, we discuss different therapeutic approaches on MDSC targeting to overcome immunosuppressive TME and enhance the efficiency of current tumor immunotherapies.
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http://dx.doi.org/10.3389/fimmu.2018.00398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207PMC
April 2019

Truncated isoform Vav3.1 is highly expressed in ovarian cancer stem cells and clinically relevant in predicting prognosis and platinum-response.

Int J Cancer 2018 04 14;142(8):1640-1651. Epub 2017 Dec 14.

Department of Obstetrics and Gynecology, Medical University Innsbruck, 6020, Innsbruck, Austria.

Vav3 is a key modulator of GTP-hydrolases of the Rho/Rac family, which are crucially involved in cell proliferation. Vav3 is alternatively spliced in full-length Vav3-alpha and N-terminal truncated Vav3.1 lacking its self-regulatory domains. The aim of our study was to estimate the clinical impact of Vav3 and all other Vav family members in ovarian cancer. Purification of a stem-cell like side-population (SP) from ovarian cancer cell lines was performed by flow cytometry/FACS. Differences in gene expression between SP and NSP were assessed by Gene Array analysis and confirmed by RT-PCR and immunoblot. In addition, Vav mRNA expression was determined in 150 epithelial ovarian cancers. Clinicopathological parameters, platinum-sensitivity and survival were analyzed and associated with Vav expression. SP fractions of ovarian cancer cell lines exhibited marked overexpression of Vav3.1 (p < 0.001). Vav1 and Vav2 did not prove to be of clinicopathologic relevance in ovarian cancer. High Vav3.1 expression correlated with higher FIGO stage and residual disease. Furthermore, Vav3.1 overexpression was associated with poor progression-free (HR = 2.820, p = 0.0001) and overall survival (HR = 2.842, p = 0.0001). Subgroup analyses revealed an impact of Vav3.1 on survival in Type-II but not in Type-I cancers. Notably, platinum-refractory cancers showed marked overexpression of Vav3.1 compared to other subsets of platinum-sensitivity (15.848 vs. 6.653, p = 0.0001). In conclusion, Vav3.1 is over-expressed in stem-cell like SP fractions and is clinically relevant in the pathophysiology of ovarian cancer. The N-terminal truncated Vav3.1 may be decisively involved in mechanisms causing genuine multi-drug resistance.
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http://dx.doi.org/10.1002/ijc.31186DOI Listing
April 2018

CCR5 Myeloid-Derived Suppressor Cells Are Enriched and Activated in Melanoma Lesions.

Cancer Res 2018 01 31;78(1):157-167. Epub 2017 Oct 31.

Skin Cancer Unit, German Cancer Research Center (DKFZ), University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany.

Accumulation of myeloid-derived suppressor cells (MDSC) in melanoma microenvironment is supported by chemokine receptor/chemokine signaling. Although different chemokines were suggested to be involved in this process, the role of CCR5 and its ligands is not established. Using a transgenic mouse melanoma model, we found an accumulation of CCR5 MDSCs in melanoma lesions associated with both increased concentrations of CCR5 ligands and tumor progression. Tumor-infiltrating CCR5 MDSCs displayed higher immunosuppressive activity than their CCR5 counterparts. Upregulation of CCR5 expression on CD11bGr1 myeloid cells was induced by CCR5 ligands and other inflammatory factors. In melanoma patients, CCR5 MDSCs were enriched at the tumor site and correlated with enhanced production of CCR5 ligands. Moreover, they exhibited a stronger immunosuppressive pattern compared with CCR5 MDSCs. Blocking CCR5/CCR5 ligand interactions increased survival of tumor-bearing mice and was associated with reduced migration and immunosuppressive potential of MDSCs in tumor lesions. Our findings define a critical role for CCR5 in recruitment and activation of MDSCs, suggesting a novel strategy for melanoma treatment. These findings validate the importance of the CCR5/CCR5 ligand axis not only for MDSC recruitment but also for further activation of their immunosuppressive functions in the tumor microenvironment, with potentially broad therapeutic implications, given existing clinically available inhibitors of this axis. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0348DOI Listing
January 2018

TMPRSS2:ERG gene fusion variants induce TGF-β signaling and epithelial to mesenchymal transition in human prostate cancer cells.

Oncotarget 2017 Apr;8(15):25115-25130

Cancer Genome Research Group, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany.

TMPRSS2:ERG (T/E) gene fusions are present in approximately 50% of all prostate cancer (PCa) cases. The expression of fusion mRNAs from distinct T/E variants is associated with clinicopathological parameters, while the underlying molecular processes remain unclear. We characterized the molecular mechanisms and functional implications caused by doxycycline (Dox)-inducible overexpression of the frequent T/E III and VI fusion variants in LNCaP cells. Induction of T/E expression resulted in increased cellular migratory and invasive potential, and reduced proliferation and accumulation in G1 phase. T/E overexpressing cells showed epithelial-to-mesenchymal transition (EMT), as demonstrated by upregulation of TGF-β and WNT pathway genes, mesenchymal markers, and increased phosphorylation of the p38 MAPK. Augmented secretion of TGF-β1 and -β2, and T/E-mediated regulation of ALK1, a member of the TGF-β receptor family, was detected. ALK1 inhibition in T/E overexpressing cells blocked p38 phosphorylation and reduced the expression of the TGF-β target genes VIM, MMP1, CDH2, and SNAI2. We found a T/E variant VI-specific induction of miR-503 associated with reduced expression of SMAD7 and CDH1. Overexpression of miR-503 led to increased levels of VIM and MMP1. Our findings indicate that TGF-β signaling is a major determinant of EMT in T/E overexpressing LNCaP cells. We provide evidence that T/E VI-specific transcriptional modulation by miR-503 accounts for differences in the activation of EMT pathway genes, promoting the aggressive phenotype of tumors expressing T/E variant VI. We suggest that ALK1-mediated TGF-β signaling is a novel oncogenic mechanism in T/E positive PCa.
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http://dx.doi.org/10.18632/oncotarget.15931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421914PMC
April 2017

Procoagulant extracellular vesicles in amniotic fluid.

Transl Res 2017 06 4;184:12-20.e1. Epub 2017 Feb 4.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria. Electronic address:

Embolization of amniotic fluid (AF) into the blood circulation leads to disseminated intravascular coagulation (DIC). Procoagulant phosphatidylserine (PS)- and tissue factor (TF)-exposing extracellular vesicles (EVs) might play an important role in AF embolism-induced DIC. It was the aim of the present study to perform analyses of the procoagulant properties of AF with a panel of functional coagulation assays and flow cytometry. We applied a prothrombinase assay (that quantifies PS exposure on EVs), an EV-associated TF activity assay, a fibrin generation assay, a thrombin generation assay, a whole blood clotting model, and flow cytometry in AF and control plasma. We found that PS exposure on EVs was 21-fold increased in AF compared with plasma. Also, EV-associated TF activity was highly increased in AF compared with plasma. AF-derived EVs activated the blood coagulation cascade via PS and TF in the fibrin and thrombin generation assays. In a whole blood clotting model, AF-derived EVs significantly shortened the clotting time from 734 ± 139 seconds in the presence to 232 ± 139 seconds in the absence of an anti-TF antibody. The contact activation pathway via factor XII (FXII) was not affected. Applying flow cytometry, a subpopulation of PS and TF EVs was identified in AF but not in control plasma. In conclusion, we investigated the effect of AF on blood coagulation and found that PS and TF EVs determine their procoagulant potential. Taken together, our data further delineate the pathomechanisms underlying AF-induced coagulopathy.
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http://dx.doi.org/10.1016/j.trsl.2017.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544525PMC
June 2017

Comparison of immunohistochemistry with PCR for assessment of ER, PR, and Ki-67 and prediction of pathological complete response in breast cancer.

BMC Cancer 2017 02 13;17(1):124. Epub 2017 Feb 13.

National Center for Tumor Diseases, University-Hospital Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.

Background: Proliferation may predict response to neoadjuvant therapy of breast cancer and is commonly assessed by manual scoring of slides stained by immunohistochemistry (IHC) for Ki-67 similar to ER and PgR. This method carries significant intra- and inter-observer variability. Automatic scoring of Ki-67 with digital image analysis (qIHC) or assessment of MKI67 gene expression with RT-qPCR may improve diagnostic accuracy.

Methods: Ki-67 IHC visual assessment was compared to the IHC nuclear tool (AperioTM) on core biopsies from a randomized neoadjuvant clinical trial. Expression of ESR1, PGR and MKI67 by RT-qPCR was performed on RNA extracted from the same formalin-fixed paraffin-embedded tissue. Concordance between the three methods (vIHC, qIHC and RT-qPCR) was assessed for all 3 markers. The potential of Ki-67 IHC and RT-qPCR to predict pathological complete response (pCR) was evaluated using ROC analysis and non-parametric Mann-Whitney Test.

Results: Correlation between methods (qIHC versus RT-qPCR) was high for ER and PgR (spearman´s r = 0.82, p < 0.0001 and r = 0.86, p < 0.0001, respectively) resulting in high levels of concordance using predefined cut-offs. When comparing qIHC of ER and PgR with RT-qPCR of ESR1 and PGR the overall agreement was 96.6 and 91.4%, respectively, while overall agreement of visual IHC with RT-qPCR was slightly lower for ER/ESR1 and PR/PGR (91.2 and 92.9%, respectively). In contrast, only a moderate correlation was observed between qIHC and RT-qPCR continuous data for Ki-67/MKI67 (Spearman's r = 0.50, p = 0.0001). Up to now no predictive cut-off for Ki-67 assessment by IHC has been established to predict response to neoadjuvant chemotherapy. Setting the desired sensitivity at 100%, specificity for the prediction of pCR (ypT0ypN0) was significantly higher for mRNA than for protein (68.9% vs. 22.2%). Moreover, the proliferation levels in patients achieving a pCR versus not differed significantly using MKI67 RNA expression (Mann-Whitney p = 0.002), but not with qIHC of Ki-67 (Mann-Whitney p = 0.097) or vIHC of Ki-67 (p = 0.131).

Conclusion: Digital image analysis can successfully be implemented for assessing ER, PR and Ki-67. IHC for ER and PR reveals high concordance with RT-qPCR. However, RT-qPCR displays a broader dynamic range and higher sensitivity than IHC. Moreover, correlation between Ki-67 qIHC and RT-qPCR is only moderate and RT-qPCR with MammaTyper® outperforms qIHC in predicting pCR. Both methods yield improvements to error-prone manual scoring of Ki-67. However, RT-qPCR was significantly more specific.
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http://dx.doi.org/10.1186/s12885-017-3111-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307758PMC
February 2017

L1CAM in the Early Enteric and Urogenital System.

J Histochem Cytochem 2017 01 12;65(1):21-32. Epub 2016 Nov 12.

Division of Clinical and Functional Anatomy, Department of Anatomy, Histology and Embryology (EJP, MJB, MB, MZ, HF), Medical University of Innsbruck, Innsbruck, Austria.

L1 cell adhesion molecule (L1CAM) is a transmembrane molecule belonging to the L1 protein family. It has shown to be a key player in axonal guidance in the course of neuronal development. Furthermore, L1CAM is also crucial for the establishment of the enteric and urogenital organs and is aberrantly expressed in cancer originating in these organs. Carcinogenesis and embryogenesis follow a lot of similar molecular pathways, but unfortunately, comprehensive data on L1CAM expression and localization in human developing organs are lacking so far. In the present study we, therefore, examined the spatiotemporal distribution of L1CAM in the early human fetal period (weeks 8-12 of gestation) by means of immunohistochemistry and in situ hybridization (ISH). In the epithelia of the gastrointestinal organs, L1CAM localization cannot be observed in the examined stages most likely due to their advanced polarization and differentiation. Despite these results, our ISH data indicate weak L1CAM expression, but only in few epithelial cells. The genital tracts, however, are distinctly L1CAM positive throughout the entire fetal period. We, therefore, conclude that in embryogenesis L1CAM is crucial for further differentiation of epithelia.
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http://dx.doi.org/10.1369/0022155416677241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256200PMC
January 2017
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