Manfred Schmitt

Technische Universität München | TUM · Frauenklinik und Poliklinik

Background: In node-negative breast cancer (NNBC), a high risk of recurrence is determined by clinico-pathological or tumor-biological assessment. Taxanes may improve adjuvant chemotherapy. Methods: NNBC 3-Europe, the first randomized phase-3 trial in node-negative breast cancer (BC) with tumor-biological risk assessment, recruited 4146 node-neg...

Aim: Since reliable response predictors to platinum-based chemotherapy in ovarian cancer (OC) are scarce, we characterize NCALD as a predictive biomarker. Materials & methods: NCALD mRNA (n = 100) and protein (n = 102) expression was analyzed in OC samples and associated with patient outcome. A stable OC cell line knockdown was generated and cellul...

A crucial mode of action of trastuzumab is the labeling of HER2-positive tumor cells for the eradication by natural killer (NK) cells, a process called antibody-dependent cellular cytotoxicity (ADCC). However, despite widespread HER2 expression among cancer entities, only a fraction, with robust HER2 overexpression, benefits from trastuzumab therap...

Significant evidence has accumulated that DNA-methylation of the paired-like homeodomain transcription factor 2 (PITX2) gene can serve as a prognostic and predictive biomarker in breast cancer. PITX2 DNA-methylation data have been obtained so far from microarray and polymerase chain reaction (PCR)-based research tests. The availability of an analyt...

Background: Tissue kallikrein-related peptidases 4, 5, 6 and 7 (KLK4-7) strongly increase the malignancy of ovarian cancer cells. Deciphering their downstream effectors, we aimed at finding new potential prognostic biomarkers and treatment targets for ovarian cancer patients. KLK4-7-transfected (OV-KLK4-7) and vector-control OV-MZ-6 (OV-VC) ovaria...

Background: Breast cancer patients at high risk for recurrence are treated with anthracycline-based chemotherapy, but not all patients do equally benefit from such a regimen. To further improve therapy decision-making, biomarkers predicting outcome are of high unmet medical need. Methods: The percent DNA methylation ratio (PMR) of the promoter gene...

International guidelines recommend anthracycline-based chemotherapy for high-risk breast cancer patients as the standard-of-care, but not all patients do equally benefit from such a chemotherapy. The novel therascreen® PITX2 RGQ PCR assay is a quantitative in vitro methylation-specific real-time PCR test (qMSP), intended for the determination of th...

PurposeGene expression of a variety of the 15 members of the KLK serine protease family is dysregulated in ovarian cancer. We aimed at determining the clinical relevance of KLK13 and KLK14 mRNA expression in tumor tissues of a homogeneous patient cohort afflicted with advanced high-grade serous ovarian cancer (FIGO stage III/IV). MethodsmRNA expres...

Triple-negative breast cancer (TNBC) constitutes a heterogeneous breast cancer subgroup with poor prognosis; survival rates are likely to be lower with TNBC compared to other breast cancer subgroups. For this disease, systemic adjuvant chemotherapy regimens often yield suboptimal clinical results. To improve treatment regimens in TNBC, identificati...

Intraabdominal tumor dissemination is a major hallmark of epithelial ovarian cancer (EOC), but the underlying mechanisms have not been fully elucidated. The CXCR3 chemokine receptor supports migration of tumor cells to metastatic sites, but its role in ovarian cancer metastasis is largely unknown. Herein, we first screened two independent cohorts o...

Cathepsin B (CTSB) is a lysosomal cysteine protease that has been linked to the progression of breast cancer, for example by activation of other proteases and tumor-promoting cytokines, thereby supporting tumor invasion and metastasis. Previously, it was shown that CTSB cleaves and inactivates C-X-C motif chemokine receptor 3 (CXCR3) chemokines. As...

Triple-negative breast cancer (TNBC), lacking the steroid hormone receptors estrogen receptor and progesterone receptor and not overexpressing the oncoprotein HER2, is characterized by its aggressive pattern and insensitivity to endocrine and HER2-directed therapy. Human kallikrein-related peptidases KLK1-15 provide a rich source of serine protease...

Triple-negative breast cancer (TNBC), lacking the steroid hormone receptors ER and PR and the oncoprotein HER2, is characterized by its aggressive pattern and insensitivity to endocrine and HER2-directed therapy. Human kallikrein-related peptidases KLK1-15 provide a rich source of serine protease-type biomarkers associated with tumor growth and can...

Most members of the kallikrein-related peptidase family have been demonstrated to be dysregulated in ovarian cancer and modulate tumor growth, migration, invasion, and resistance to chemotherapy. In the present study, we assessed the mRNA expression levels of KLK6 and KLK8 by quantitative PCR in 100 patients with advanced serous ovarian cancer FIGO...

Background Triple-negative breast cancer (TNBC) with a BRCA1-like molecular signature has been demonstrated to remarkably respond to platinum-based chemotherapy and might be suited for a future treatment with poly(ADP-ribose)polymerase (PARP) inhibitors. In order to rapidly assess this signature we have previously developed a multiplex-ligation-dep...

Zielsetzung: Die Peritonealmetastasierung stellt das entscheidende klinische Problem beim Ovarialkarzinom dar. Chemokinrezeptoren vermitteln normalerweise die Migration von Leukozyten, konnen aber auch von Tumorzellen zur Metastasierung „missbraucht“ werden. Ein moglicher Kandidat ist der CXCR3-Chemokinrezeptor, dessen Rolle in Ovarialkarzinomzelle...

Background Due to lack of a targeted therapy for the triple-negative breast cancer (TNBC) patients, it is important to explore this aggressive breast cancer type in more detail and to establish novel therapeutic approaches. TNBC is defined negative for the protein expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal...

Background: Tumour-infiltrating lymphocytes (TILs) are associated with improved survival in several epithelial cancers. The two chemokines CXCL9 and CXCL10 facilitate chemotactic recruitment of TILs, and their intratumoral accumulation is a conceivable way to improve TIL-dependent immune intervention in cancer. However, the prognostic impact of CX...

The triple-negative breast cancer (TNBC) is a very aggressive tumor type often occurring in young women and is associated with a bad prognosis for the patients. TNBC lacks established targets for breast cancer therapy, such as the estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2). Therefore,...

In serous ovarian cancer, the clinical relevance of tumor cell-expressed plasmin(ogen) (PLG) has not yet been evaluated. Due to its proteolytic activity, plasmin supports tumorigenesis, however, angiostatin(-like) fragments, derived from PLG, can also function as potent antitumorigenic factors. In the present study, we assessed PLG protein expressi...

Members of the human kallikrein-related peptidase (KLK) family, including KLK5, have been reported to play an important role in ovarian cancer progression. In the present study, we assessed KLK5 protein expression in ovarian cancer tissues by immunohistochemistry (IHC) and ELISA, and analyzed its association with clinicopathologic parameters and di...

Methods: We evaluated uPAR and its interaction partners (uPAR-interactome) by immunohistochemistry (IHC) in tissue microarrays (TMA) prepared from ~300 TNBC tumor tissue specimens and in the TNBC model cell lines BT549 and MDA-MB231. Protein expression of 25 different factors constituting the uPAR-interactome was evaluated by IHC; several of the u...

Little is known about epigenetics and its possible role in atherosclerosis. We here analysed histone and DNA methylation and the expression of corresponding methyltransferases in early and advanced human atherosclerotic carotid lesions in comparison to healthy carotid arteries. Western Blotting was performed on carotid plaques from our biobank with...

miR-221/-222 and components of the urokinase-type plasminogen activator system (uPAS) are associated with metastasis and poor prognosis in breast cancer, including the triple-negative subtype (TNBC). Modification of components of uPAS and involved miRNAs may contribute to targeted therapy for breast cancer patients. miR-221-/-222-overexpressing or...

We have read with great interest the article by Kadoch and colleagues ([1][1]). Their pharmacokinetic model indicates rapid distribution of intraventricular rituximab from cerebrospinal fluid (CSF) into neural tissues and serum. These findings may have more general implications for intrathecal (IT

Following primary debulking surgery, the presence of a residual tumor mass is one of the most important prognostic factors in ovarian cancer. In a previous study, we established the OVSCORE, an algorithm to predict surgical outcome, based on the clinical factors of nuclear grading and ascitic fluid volume, plus the cancer biomarkers, kallikrein-rel...

An essential and so far unresolved factor influencing the evolution of cancer and the clinical management of patients is intra-tumor clonal and phenotypic heterogeneity. However, the de novo identification of tumor subpopulations is a so far challenging, if not an unresolved, task. Here we present the first systematic approach for the de novo disco...

Urokinase plasminogen activator (uPA) is an extracellular matrix-degrading protease involved in cancer invasion and metastasis, interacting with plasminogen activator inhibitor-1 (PAI-1), which was originally identified as a blood-derived endogenous fast-acting inhibitor of uPA. At concentrations found in tumor tissue, however, both PAI-1 and uPA p...

MALDI mass spectrometry imaging (MSI) has rapidly established itself as a powerful biomarker discovery tool. To date no formal investigation has assessed the center-to-center comparability of MALDI MSI experiments, an essential step for it develop into a new diagnostic method. In order to test such capabilities we have performed a multicenter study...

Abstract Gynecological cancers, including malignant tumors of the ovaries, the endometrium and the cervix, account for approximately 10% of tumor-associated deaths in women of the Western world. For screening, diagnosis, prognosis, and therapy response prediction, the group of enzymes known as serine (Ser-)proteases show great promise as biomarkers...

Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and...

Tumor tissue-associated KLKs (kallikrein-related peptidases) are clinically important biomarkers that may allow prognosis of the cancer disease and/or prediction of response/failure of cancer patients to cancer-directed drugs. Regarding the female/male reproductive tract, remarkably, all of the fifteen KLKs are expressed in the normal prostate, bre...

Background: MiR-221/-222 are frequently overexpressed in breast cancer and are associated with increased malignancy. The specific modification of microRNAs (miRNAs) expression could be a promising strategy in breast cancer therapy, leading to the suppression of tumourigenic processes in tumour cells. Methods: MiR-221/-222 expressions were analysed...

Background: Genomic rearrangements at the fragile site FRA1E may disrupt the dihydropyrimidine dehydrogenase gene (DPYD) which is involved in 5-fluorouracil (5-FU) catabolism. In triple-negative breast cancer (TNBC), a subtype of breast cancer frequently deficient in DNA repair, we have investigated the susceptibility to acquire copy number variati...

Introduction: The expression of miR-221 and -222 is frequently altered in invasive breast cancer and in breast cancer cell lines. We aimed to determine the prognostic and/or therapeutic impact of miR-221/222 expression and its association with tumor progression and metastasizing processes. Experimental procedures: We investigated the expression of...

Abstract Expression of the kallikrein-related peptidase KLK7 is dysregulated in ovarian cancer. We assessed KLK7 expression by ELISA and quantitative immunohistochemistry and analysed its association with clinicopathological parameters and patients' outcome. KLK7 antigen concentrations were determined in tumour tissue extracts of 98 ovarian cancer...

Chemotherapeutic drugs kill cancer cells, but it is unclear why this happens in responding patients but not in non-responders. Proteomic profiles of patients with oesophageal adenocarcinoma may be helpful in predicting response and selecting more effective treatment strategies. In this study, pre-therapeutic oesophageal adenocarcinoma biopsies were...

Kallikrein-related peptidases (KLK), which represent a major tissue-associated proteolytic system, stand for a rich source of biomarkers that may allow molecular classification, early diagnosis and prognosis of human malignancies as well as prediction of response or failure to cancer-directed drugs. International research points to an important rol...

Background Invasion factors uPA/PAI-1 are guideline-recommended (ASCO, AGO) biomarkers for decision support regarding adjuvant chemotherapy (CTX) in primary breast cancer (BC). Methods Potential savings in direct, per-patient expected costs of two leading CTX regimens (6xFEC or 3xFEC-3xDOC) resulting from uPA/PAI-1 test were calculated from a Germa...

Aim: Final 10-year analysis of the prospective randomised Chemo-N0 trial is presented. Based on the Chemo-N0 interim results and an European Organisation for Research and Treatment of Cancer (EORTC) pooled analysis (n=8377), American Society of Clinical Oncology (ASCO) and Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) guidelines recommend inv...

Breast cancer is the most common malignancy in women of the Western world. One prominent feature of breast cancer is the co- and overexpression of human epidermal growth factor receptor 2 (HER2) and protein tyrosine kinase 6 (PTK6). According to the current clinical cancer therapy guidelines, HER2-overexpressing tumors are routinely treated with tr...

Withdrawn by Author Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-02.

mRNA levels of the urokinase receptor splice variant uPAR-del4/5 are associated with prognosis in breast cancer. Its overexpression in cancer cells affects tumor biologically relevant processes. In the present study, individual breast cancer cell clones displaying low vs. high uPAR-del4/5 expression were analyzed demonstrating that uPAR-del4/5 lead...

Background Rab proteins constitute a large family of monomeric GTP-binding proteins that regulate intracellular vesicle transport. Several Rab proteins, including rab31, have been shown to affect cancer progression and are related with prognosis in various types of cancer including breast cancer. Recently, the gene encoding rab31 was found to be ov...

Figure S2. The constitutively active rab31-mutant Q64L, but not the inactive form rab31-ΔCC, induces cell growth and reduces cell adhesion, when overexpressed in MDA-MB-231 breast cancer cells. (A) Overexpression of rab31 mutants in breast cancer cells. MDA-MB-231 cells were stably transfected with rab31 expression plasmids encoding either the cons...

Figure S1. Analysis of MDA-MB-231 cell transfectants for rab31 expression by immunofluorescence. After overnight growth on fibronectin-coated glass slides, the cell monolayers were fixed and permeabilized with PBS containing 4% (w/v) paraformaldehyde, 0.025% (w/v) saponin. After incubation, the rabbit antibody directed to rab31 was detected with Al...

The isolation of circulating tumor cells (CTCs) from the blood of patients afflicted with solid malignant tumors becomes increasingly important as it may serve as a 'liquid biopsy' with the potential of monitoring the course of the cancer disease and its response to cancer therapy, with subsequent molecular characterization. For this purpose, we fu...

Several members of the human kallikrein-related peptidase family, including KLK6, are up-regulated in ovarian cancer. High KLK6 mRNA or protein expression, measured by quantitative polymerase chain reaction and enzyme-linked immunoassay, respectively, was previously found to be associated with a shortened overall and progression-free survival (OS a...

The increasing demand for personalized cancer therapy requires a strong, intense, and continuous collaboration between pre-clinical and clinical investigators. As a part of the EORTC Translational Research Divison, the EORTC PathoBiology Group (EORTC PBG), focuses on discovery and validation of cancer biomarkers, providing both scientific evidence...

[Background] C2P is an assay measuring specific activities (SA; kinase activity compensated by its protein expression) of cyclin-dependent kinases CDK1 and CDK2 by examining a small piece of fresh-frozen tumor tissue. We reported previously that the C2P risk score given by CDK1SA and CDK2SA is a potent prognostic factor in node-negative breast canc...

In murine breast cancer models, the two interferon-gamma (IFN-γ) inducible chemokines and CXC-chemokine receptor 3 (CXCR3) receptor ligands, monokine induced by γ-interferon (CXCL9) and interferon-γ-inducible protein-10 (CXCL10) impair tumor growth and metastasis formation through recruitment of natural killer (NK) cells and tumor-suppressive T lym...

Epigenetic drugs are promising add-ons to cancer treatment; still, adverse effects concerning tumour promotion have been reported occasionally. In this in vitro study, we investigated the effect of combination treatment of decitabine with anthracycline-based chemotherapy [5-fluorouracil plus epirubicine plus cyclophosphamide (FEC)] on viability and...

Histology-based classifications and clinical parameters of head and neck squamous cell carcinoma (HNSCC) are limited in their clinical capacity to provide information on prognosis and treatment choice of HNSCC. The primary aim of this study was to analyse Y-box-binding protein-1 (YB-1) protein expression in different grading groups of HNSCC patient...

45 Background: In murine cancer models, the two IFN-γ inducible chemokines CXCL9 and CXCL10, those bind to the common receptor CXCR3, recruit NK cells and tumor-suppressive lymphocytes into the tumor site and impair tumor growth and metastatic spread. In human breast cancer (BC), we and others have shown that high levels of CXCL9 mRNA correlate wit...

Alternative splicing has been shown to be deregulated in cancer and a link to growth stimulation has been established. Here we describe transmembrane and extracellular matrix-related targets generated by alternative splicing with a restricted pattern of expression in normal tissues and a deregulated pattern of expression in cancer as possible targe...

High tumor tissue mRNA expression of the tumor biological factors uPAR, uPAR-del4/5, or rab31 is associated with shorter distant metastasis-free and overall survival in breast cancer patients. To evaluate whether these factors are also clinically relevant in ovarian cancer, we quantified the respective mRNA levels in primary tumor tissue of advance...

Fragestellung: In Maustumormodellen locken die beiden durch IFN-γ induzierbaren Chemokine und CXCR3-Rezeptor-Liganden CXCL9 und CXCL10 tumor-suppressive Lymphozyten chemotaktisch in den Tumor und bremsen so Tumorwachstum und Metastasierung. Dementsprechend korreliert eine erhohte intratumorale Expression dieser Chemokine auch in Brusttumoren des Me...

Effective cancer biomarkers for early detection, prognosis, or therapy response prediction are urgently needed in ovarian cancer. Kallikrein-related peptidases, including KLK5, have been reported to play an important role in the course of the disease. KLK5 antigen content was determined by enzyme-linked immunosorbent assay in ovarian cancer patient...

Clinical research on cancer biomarkers is essential in understanding recent discoveries in cancer biology and heterogeneity of the cancer disease. However, there are only a few examples of clinically useful studies that have identified cancer biomarkers with clinical benefit. Urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen...

uPAR, the three-domain membrane receptor of the serine protease urokinase, plays a crucial role in tumor growth and metastasis. Several mRNA splice variants of this receptor have been reported. One of these, uPAR-del4/5, lacking exons 4 and 5, and thus encoding a uPAR form lacking domain DII, is specifically overexpressed in breast cancer and repre...

Introduction IFN γ inducible chemokine CXCL9 impairs tumor growth and metastasis formation through recruitment of natural killer (NK) cells and tumor suppressive T lymphocytes in murine breast cancer models. In human breast cancer CXCL9 mRNA expression correlates with response to different chemotherapeutic regimens and tumor infiltrating lymphocyte...

L1CAM expression and proliferation analysis of transduced SKOV3ip-lacZ cells. SKOV3ip-lacZ cells were transduced with FL- or SV-L1CAM cDNA or with an empty vector. A. Western Blot analysis of L1CAM showed increased expression of L1CAM variants after gene transfer. The two bands at 220 kDa and 200 kDa are due to differential glycosylation status of...

L1CAM expression and proliferation analysis of transduced L-CI.5s cells. L-CI.5s cells were transduced with FL- or SV-L1CAM cDNA or with an empty vector. A. Western Blot analysis of L1CAM showed increased expression of L1CAM variants after gene transfer. The two bands at 220 kDa and 200 kDa are due to differential glycosylation status of L1CAM. B....

Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so f...

Today, more than 70% of patients with primary node-negative breast cancer are cured by local therapy alone. Many patients receive overtreatment by adjuvant chemotherapy due to inadequate risk assessment. So far, few clinical trials have prospectively evaluated tumor biology based prognostic factors. Risk assessment by a biological algorithm includi...

Bone defects due to malignant tumor often lead to repeated surgery or amputation. Thus, a major objective in orthopedic surgery is the extracorporeal devitalization of tumor-bearing bone segments following reimplantation. Extracorporeal irradiation or autoclaving are possible methods even though they may cause severe loss of biomechanical and biolo...

The prognostic and/or predictive value of the cancer biomarkers, urokinase-type plasminogen activator (uPA) and its inhibitor (plasminogen activator inhibitor [PAI]-1), determined by ELISA in tumor-tissue extracts, was demonstrated for several cancer types in numerous clinically relevant retrospective or prospective studies, including a multicenter...

Primary tumor levels of serine proteases of the kallikrein-related peptidases (KLK) family as well as urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 impact disease course in ovarian cancer. The changes in levels of these factors from primary tumor to omentum metastasis ('level differentials') could thus be associated with metast...

The urokinase-type plasminogen activator (uPA) and its main inhibitor PAI-1 play key roles in tumor-associated processes such as the degradation of the extracellular matrix (ECM), tissue remodeling, cell adhesion and migration. Elevated expression of both molecules is known to correlate with negative outcomes in node negative breast cancer. To date...

In cancer, the serine protease urokinase-type plasminogen activator, its inhibitor (plasminogen activator inhibitor type-1) and the receptor (CD87), among other proteolytic factors, are involved in tumor cell dissemination and turnover of the extracellular matrix. Unsurprisingly, a battery of very uniform data, amassed since the end of the 1990s, h...

Protein tyrosine kinase 6 (PTK6; breast tumour kinase) is overexpressed in up to 86% of the invasive breast cancers, and its association with the oncoprotein human epidermal growth factor receptor 2 (HER2) was shown in vitro by co-precipitation. Furthermore, expression of PTK6 in tumours is linked with the expression of HER2. In this study, we used...