{"id":27514,"date":"2020-06-12T10:00:00","date_gmt":"2020-06-12T08:00:00","guid":{"rendered":"https:\/\/www.embl.org\/news\/?p=27514"},"modified":"2024-03-22T13:22:06","modified_gmt":"2024-03-22T12:22:06","slug":"liver-metastases","status":"publish","type":"post","link":"https:\/\/www.embl.org\/news\/science\/liver-metastases\/","title":{"rendered":"Blood pressure drug improves response to cancer therapy"},"content":{"rendered":"\n

Scientists at Heidelberg University Hospital and the European Molecular Biology Laboratory (EMBL) have discovered that a drug to lower blood pressure alters the tissue characteristics of secondary tumours, or metastases, from colon cancer. The \u2018stiffness\u2019 of these metastases has an effect on the success of cancer therapies. The results are published in Cancer Cell.<\/p>\n\n\n\n

Heidelberg scientists have found a new potential target for the treatment of therapy-resistant liver metastases in colon cancer: the \u2018tissue stiffness\u2019 of the metastases. The teams, from the Surgical University Hospital and EMBL, discovered that the stiffer the tissue of a patient\u2019s metastasis, the worse would be their response to therapy with a common cancer drug. Surprisingly, certain drugs to lower blood pressure seem able to remedy the situation. In patients who were already taking them to regulate blood pressure, the metastases were softer and had a poorer blood supply. They also responded better to the cancer drug, and the patients had a better chance of survival.<\/p>\n\n\n\n

\u201cThere are indications that it behaves similarly to other types of tumours. It is therefore worthwhile, in the search for new cancer therapies, to focus even more closely on the tissue properties, such as tissue stiffness of tumours, their metastases, and surrounding tissue,\u201d says senior author Thomas Schmidt, head of the Metastatic Tumor Microenvironment Research Group at the Surgical University Hospital in Heidelberg. \u201cWe used atomic force spectroscopy to measure tissue stiffness. This makes changes in the surface mechanics visible. By combining it with primary tissue, we were able to test the role of different treatments on the tissue stiffness of metastases,\u201d explains Alba Diz-Mu\u00f1oz, group leader at EMBL<\/a>. In a follow-up study, the scientists now plan to investigate the benefits of a combination therapy of anticancer and blood pressure drugs in more detail.<\/p>\n\n\n\n

Stiffness of metastases promotes their growth<\/h3>\n\n\n\n

Colon cancer often spreads to the liver: at the time of diagnosis, 20\u201330% of patients already have liver metastases. Overall, they occur in more than half of all patients during the course of the disease. \u201cSince the actual tumour in the colon and rectum can be easily treated surgically, metastases \u2013 especially liver metastases \u2013 are the major cause of death in this type of cancer,\u201d says Schmidt. \u201cIn order to improve the patients’ chances of survival, we need new therapeutic approaches that are adapted to the special characteristics of metastases.\u201d<\/p>\n\n\n\n

The special tissue characteristics of liver metastases are caused by altered connective tissue cells, so-called fibroblasts. Among other things, these fibroblasts release collagen, a protein that gives cartilage, tendons, and ligaments their tensile strength. Collagen fibres can also contract, making the tissue lose elasticity and become stiffer. This promotes the inward migration of blood vessels and thus the growth of metastases. \u201cThe firmer tissue around the metastases presumably presses on the blood vessels that run there and gives the signal for branching,\u201d explains Schmidt This effect counteracts the drug bevacizumab, which is used precisely to inhibit the formation of blood vessels in cancerous tissue. The therapeutic effect fizzles out.<\/p>\n\n\n\n

This is the point at which antihypertensives \u2013 drugs for the treatment of high blood pressure \u2013 unexpectedly take effect, as the scientists report. It was already known that colon cancer patients taking these so-called renin\u2013angiotensin inhibitors have a better chance of survival when treated with bevacizumab, but not why. Schmidt and Diz-Mu\u00f1oz\u2019s teams have now discovered that these drugs block the altered fibroblasts of the metastases \u2013 both their contraction and collagen secretion \u2013 and thus the stiffening of the tissue. The anticancer drug can then have a more powerful effect.<\/p>\n\n\n\n

\u201cWhat is special about this study is that we have not demonstrated the effect of the antihypertensive drug on the metastases in animal experiments, but rather on patient tissue newly obtained during surgery. We will be able to build directly on this in subsequent studies,\u201d says Schmidt.<\/p>\n\n\n

\n\n\n

Blutdrucksenker k\u00f6nnte Therapieansprechen von Lebermetastasen verbessern<\/h2>\n\n\n\n

Wissenschaftler des Universit\u00e4tsklinikums Heidelberg und des Europ\u00e4ischen Laboratoriums f\u00fcr Molekularbiologie (EMBL) haben entdeckt, dass ein Medikament zur Senkung des Blutdrucks die Gewebemerkmale von Sekund\u00e4rtumoren oder Metastasen des Dickdarmkrebses ver\u00e4ndert. Die “Steifheit” dieser Metastasen wirkt sich auf den Erfolg von Krebstherapien aus. Die Ergebnisse sind in Cancer Cell ver\u00f6ffentlicht.<\/p>\n\n\n\n

Heidelberger Wissenschaftler haben ein neues potentielles Angriffsziel f\u00fcr die Behandlung von therapieresistenten Lebermetastasen bei Dickdarmkrebs gefunden: die \u201eGewebesteifigkeit\u201c der Tumorabsiedlungen. Die Teams der Chirurgischen Universit\u00e4tsklinik und des EMBL entdeckten an entfernten Metastasen von Patienten, dass diese umso schlechter auf die Therapie mit einem g\u00e4ngigen Krebsmedikament ansprachen, je steifer ihr Gewebe war. \u00dcberraschende Abhilfe schaffen offensichtlich bestimmte Mittel gegen Bluthochdruck: Bei Patienten, die diese ohnehin zur Blutdruckregulation einnahmen, waren die Metastasen weicher und schlechter durchblutet. Sie sprachen besser auf das Krebsmedikament an, die Patienten hatten bessere \u00dcberlebenschancen.<\/p>\n\n\n\n

\u201eEs gibt Hinweise, dass es sich bei anderen Tumorarten \u00e4hnlich verh\u00e4lt. Es lohnt sich daher, bei der Suche nach neuen Krebstherapien die Gewebeeigenschaften, wie beispielsweise die Gewebesteifigkeit, von Tumoren, ihren Metastasen und des umgebenden Gewebes noch st\u00e4rker in den Blick zu nehmen\u201c, erl\u00e4utert Seniorautor Thomas Schmidt, Leiter der \u201eMetastatic Tumor Microenvironment Reserach Group\u201c an der Chirurgischen Universit\u00e4tsklinik Heidelberg. \u201eUm die Gewebesteifigkeit zu messen verwendeten wir Rasterkraftspektroskopie. Diese macht Ver\u00e4nderungen in der Oberfl\u00e4chenmechanik sichtbar. Durch die Kombination mit Prim\u00e4rgewebe konnten wir so die Rolle verschiedener Behandlungen auf die Gewebesteifigkeit von Metastasen testen\u201c, erkl\u00e4rt Alba Diz-Mu\u00f1oz, Gruppenleiterin am EMBL<\/a>. In einer Folgestudie wollen die Wissenschaftler nun den Nutzen einer Kombinationstherapie von Krebs- und Blutdruckmedikament genauer untersuchen.<\/p>\n\n\n\n

Steifigkeit der Metastasen f\u00f6rdert deren Wachstum<\/h3>\n\n\n\n

Dickdarmkrebs streut h\u00e4ufig in die Leber: Bei der Diagnose finden sich bei 20 bis 30 Prozent der Patienten bereits Lebermetastasen, insgesamt treten sie bei mehr als der H\u00e4lfte aller Patienten im Laufe der Erkrankung auf. \u201eDa der eigentliche Tumor im Dick- und Enddarm chirurgisch gut zu behandeln ist, sind Metastasen, insbesondere Lebermetastasen die Haupttodesursache bei dieser Krebsart\u201c, so Schmidt. \u201eUm die \u00dcberlebenschance der Patienten zu verbessern, brauchen wir neue Therapieans\u00e4tze, die an die besonderen Eigenschaften der Metastasen angepasst sind.\u201c<\/p>\n\n\n\n

Verursacher der besonderen Gewebeeigenschaften der Lebermetastasen sind ver\u00e4nderte Bindegewebszellen, sogenannte Fibroblasten. Diese geben u.a. Kollagen ab, ein Eiwei\u00df, das Knorpel, Sehnen und B\u00e4ndern ihre Zugfestigkeit verleiht, und ziehen sich zudem zusammen: Das Gewebe verliert an Elastizit\u00e4t und wird steifer. Das f\u00f6rdert das Einwandern von Blutgef\u00e4\u00dfen und damit das Wachstum der Metastasen. \u201eDas festere Gewebe rund um die Metastasen dr\u00fcckt vermutlich auf die dort verlaufenden Blutgef\u00e4\u00dfe und gibt das Signal zur Verzweigung\u201c, erl\u00e4utert der Chirurg. Diese Reaktion wirkt dem Medikament Bevacizumab entgegen, das eben genau eingesetzt wird, um die Ausbildung von Blutgef\u00e4\u00dfen in Krebsgewebe zu hemmen. Die therapeutische Wirkung verpufft.<\/p>\n\n\n\n

An diesem neuralgischen Punkt setzen unerwartet Medikamente zur Behandlung von Bluthochdruck an, wie die Heidelberger Wissenschaftler berichten. Dass Darmkrebs-Patienten, die diese sogenannten Renin-Angiotensin-Inhibitoren (anti-RAS) einnehmen, bei einer Krebstherapie mit Bevacizumab bessere \u00dcberlebenschancen haben, ist bekannt, nicht aber warum. Das Team um Schmidt entdeckte nun: Die Blutdrucksenker blockieren die ver\u00e4nderten Fibroblasten der Metastasen \u2013 sowohl deren Kontraktion als auch die Kollagen-Absonderung \u2013 und damit die Versteifung des Gewebes. Das Krebsmedikament kann seine Wirkung besser entfalten.<\/p>\n\n\n\n

\u201eDas Besondere an dieser Studie ist, dass wir die Wirkung des Blutdrucksenkers auf die Metastasen nicht im Tierversuch, sondern an jeweils bei den OPs neu gewonnenem Patientengewebe nachgewiesen haben. Darauf k\u00f6nnen wir in folgenden Studien unmittelbar aufbauen\u201c, so Schmidt.<\/p>\n","protected":false},"excerpt":{"rendered":"

Scientists discovered that antihypertensive agent alters the tissue characteristics of colon cancer metastases. 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