Gerd Bauerschmitz

Inhibition of SDF-1/CXCR4-induced epithelial-mesenchymal transition by kisspeptin-10

Recently we have shown that breast cancer cell invasion was dramatically increased when co-cultured with MG63 cells. In addition we have generated mesenchymal transformed MCF-7 breast cancer cells (MCF-7-EMT), showing significantly increased invasion in contrast to wild type MCF-7 cells (MCF-7 WT). In this study we have analyzed whether stromal derived factor-1 (SDF-1) is responsible for MCF-7 and T-47-D breast cancer cell invasion and epithelial–mesenchymal-transition (EMT). In addition we have analyzed whether kisspeptin-10 (KP-10) treatment affects SDF-1-induced invasion and EMT. Invasion was quantified by assessment of MCF-7 and T-47-D breast cancer cell migration rate through an artificial basement membrane in a modified Boyden chamber during co-culture with MG63 cells or after treatment with SDF-1α, SDF-1β or the combination of both isoforms. Induction of EMT was verified by analysis of protein expression of epithelial marker E-cadherin (CDH1) and mesenchymal markers N-cadherin (CDH2) and Vimentin (VIM). The role of SDF-1 for invasion and induction of EMT in breast cancer cells was analyzed by blocking SDF-1 secretion during co-culture with MG63 cells. In addition effects of KP-10 treatment on SDF-1-induced invasion and EMT were analyzed. Breast cancer cell invasion was significantly increased when co-cultured with MG63 cells. During co-culture SDF-1 protein expression of MG63 cells was significantly induced. The increased breast cancer cell invasion could be blocked by anti-SDF-1 antibodies. Treatment of breast cancer cells in monoculture (without MG63) with SDF-1α, SDF-1β or the combination of both isoforms resulted in a significant escalation of breast cancer cell invasion and induction of EMT. Protein expression of mesenchymal markers CDH2 and VIM was clearly elevated, whereas protein expression of epithelial marker CDH1 was clearly decreased. The SDF-1-induced increase of cell invasion was significantly reduced after treatment with KP-10. In addition, induction of EMT was inhibited. Furthermore, protein expression of the binding site of SDF-1, CXC-motive-chemokine receptor 4 (CXCR-4), was reduced by KP-10. Treatment of MCF-7-EMT cells with KP-10 resulted in a significant drop of cell invasion and CXCR-4 protein expression. Our findings suggest that SDF-1 plays a major role in breast cancer invasion and EMT. SDF-1-induced invasion and EMT can be inhibited by KP-10 treatment by down-regulating CXCR-4 expression.

Invasion and increased expression of S100A4 and CYR61 in mesenchymal transformed breast cancer cells is downregulated by GnRH.

S100 calcium binding protein A4 (S100A4) and cysteine-rich angiogenic inducer 61 (CYR61) play important roles in epithelial-mesenchymal-transition (EMT), invasion and metastasis by promoting cancer cell motility. Recently we were able to show that invasion of GnRH receptor-positive breast cancer cells is time- and dose-dependently reduced by GnRH analogs. We have now analyzed whether GnRH treatment affects S100A4 and CYR61 in mesenchymal transformed breast cancer cells. S100A4 and CYR61 expression was analyzed using RT-PCR. Invasion was quantified by assessment of breast cancer cell migration rate through an artificial basement membrane. The role of S100A4 and CYR61 in invasion of breast cancer cells was analyzed by neutralizing their biological activity. Expression of S100A4, CYR61 and GnRH receptor in human breast cancers, normal and other non-malignant breast tissues was analyzed by immuno-histochemistry. Invasion and expression of S100A4 and CYR61 in MDA-MB-231 breast cancer cells were significant higher as compared with MCF-7 breast cancer cells. Invasion and expression of S100A4 and CYR61 were significantly increased in mesenchymal transformed MCF-7 cells (MCF-7-EMT). The increased invasion of MCF-7-EMT cells could be reduced by anti-S100A4 and anti-CYR61 antibodies. In addition, invasion of MDA-MB-231 cells was decreased by anti-S100A4 and anti-CYR61 antibodies. Treatment of MCF-7-EMT and MDA-MB-231 cells with GnRH agonist Triptorelin resulted in a significant decrease of invasion and expression of S100A4 and CYR61. Both, S100A4 and CYR61 were found highly expressed in biopsy specimens of breast hyperplasia and malignant breast cancers. GnRH receptor expression was detectable in approximately 71% of malignant breast cancers. Our findings suggest that S100A4 and CYR61 play major roles in breast cancer invasion. Both, invasion and expression of S100A4 and CYR61 can be inhibited by GnRH treatment.

Interdisciplinary Diagnosis, Therapy and Follow-up of Patients with Endometrial Cancer. Guideline (S3-Level, AWMF Registry Nummer 032/034-OL, April 2018) – Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer

Summary The first German interdisciplinary S3-guideline on the diagnosis, therapy and follow-up of patients with endometrial cancer was published in April 2018. Funded by German Cancer Aid as part of an Oncology Guidelines Program, the lead coordinators of the guideline were the German Society of Gynecology and Obstetrics (DGGG) and the Gynecological Oncology Working Group (AGO) of the German Cancer Society (DKG). Purpose The use of evidence-based, risk-adapted therapy to treat low-risk women with endometrial cancer avoids unnecessarily radical surgery and non-useful adjuvant radiotherapy and/or chemotherapy. This can significantly reduce therapy-induced morbidity and improve the patientʼs quality of life as well as avoiding unnecessary costs. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimal surgical radicality together with the appropriate chemotherapy and/or adjuvant radiotherapy where required. The evidence-based optimal use of different therapeutic modalities should improve survival rates and the quality of life of these patients. The S3-guideline on endometrial cancer is intended as a basis for certified gynecological cancer centers. The aim is that the quality indicators established in this guideline will be incorporated in the certification processes of these centers. Methods The guideline was compiled in accordance with the requirements for S3-level guidelines. This includes, in the first instance, the adaptation of source guidelines selected using the DELBI instrument for appraising guidelines. Other consulted sources include reviews of evidence which were compiled from literature selected during systematic searches of literature databases using the PICO scheme. In addition, an external biostatistics institute was commissioned to carry out a systematic search and assessment of the literature for one area of the guideline. The identified materials were used by the interdisciplinary working groups to develop suggestions for Recommendations and Statements, which were then modified during structured consensus conferences and/or additionally amended online using the DELPHI method with consent being reached online. The guideline report is freely available online. Recommendations Part 1 of this short version of the guideline presents recommendations on epidemiology, screening, diagnosis and hereditary factors, The epidemiology of endometrial cancer and the risk factors for developing endomentrial cancer are presented. The options for screening and the methods used to diagnose endometrial cancer including the pathology of the cancer are outlined. Recommendations are given for the prevention, diagnosis, and therapy of hereditary forms of endometrial cancer.

Palliativmedizinische Konzepte beim Ovarialkarzinom

ZusammenfassungTrotz aller therapeutischen Fortschritte versterben die meisten Ovarialkarzinompatientinnen an dieser Erkrankung. Das Behandlungsteam muss rechtzeitig den Einsatz wenig bzw. nicht wirksamer Chemotherapien zurücknehmen und stattdessen professionell die sehr beeinträchtigenden Symptome der fortschreitenden Erkrankung hinauszögern bzw. behandeln. Zu diesen gehören u. a. Obstipation, Darmobstruktion, Erbrechen, Tenesmen, Anorexie, Aszites, Ödeme, Angst, Depression und Schmerzen. Eine enge und frühzeitige Kooperation zwischen gynäkologischen Onkologen und Palliativmedizinern ist hierfür die Voraussetzung.AbstractIn spite of all recent advances in the treatment of patients with ovarian cancer, most of these women ultimately die of the disease. The treatment team must revoke the treatment aims in a timely manner and avoid chemotherapy with limited or non-existing efficacy to improve the patient quality of life. Instead they should put the focus on the professional treatment of the impairing symptoms of the progressive disease, including obstipation, bowel obstruction, vomiting, tenesmus, anorexia, ascites, edema, fear, depression and pain. An early and close cooperation between gynecological oncologists and palliative care specialists is a prerequisite.

Palliativmedizinische Konzepte beim Mammakarzinom@@@Palliative medical concepts in breast cancer

ZusammenfassungDie Erstellung eines adäquaten palliativmedizinischen Konzepts beim metastasierten Mammakarzinom stellt höchste Anforderungen an die onkologisch tätigen Behandlungsteams und an die Patientin. Erstes Ziel ist der Erhalt der Lebensqualität. Es gilt, Symptome möglichst früh zu erfassen, nebenwirkungsarm und der Situation angepasst zu lindern und präventiv Komplikationen zu verhindern. Therapiestrategien müssen stadiengerecht in enger Kooperation interdisziplinär konzipiert werden, multimodal und flexibel sein. Im Entscheidungsprozess muss die Patientin von Anfang an aktiv eingebunden sein, um gemeinsam Therapieziele zu definieren. Psychosoziale, physiotherapeutische, pflegerische und komplementäre Maßnahmen müssen der Patientin aufgezeigt werden. Ansprechen, Wirkungen und Nebenwirkungen der Therapien, aber auch zuwartendes Verhalten müssen in regelmäßigen Abständen evaluiert werden. Kumulative Toxizitäten, abnehmende Wirksamkeiten und Resistenzen gegenüber medikamentösen Therapien sind im Verlauf zu berücksichtigen.AbstractThe construction of an adequate palliative medical concept in treating metastasized advanced breast cancer places highest demands on both the treating oncological team and the patient. The first target is to preserve the quality of life. For this it is necessary to recognize the symptoms as early as possible in order to alleviate side effects adapted to the situation and to prophylactically prevent complications. The strategies for therapy must be stage-dependent and designed in a close interdisciplinary cooperation and multimodal while being flexible. The patient must be actively involved in the decision-making process from the beginning in order to jointly define the aims of therapy. Psychosocial, physiotherapeutic, nursing and complementary measures must be explained to the patient. The response to, effects and side effects of treatment and also patiently waiting behavior must be evaluated at regular intervals. Cumulative toxicity, decreasing effectiveness and resistance to medication therapy must be taken into consideration during the course of therapy.