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Biomarkers for the identification of metastases

Prof. Dr. Heike Allgayer, a surgeon and molecular biologist from Heidelberg, is investigating the molecular processes of the formation of tumour metastases. A major objective of her research is to find specific biomarkers that enable the early identification of metastases and to monitor the outcome of therapy. She has already received numerous prizes for her achievements.

Prof. Dr. Heike Allgayer © Mannheim University Hospital

The major focus of Professor Dr. Heike Allgayer's research is the molecules and biochemical processes that enable tumour cells to metastasise.

Prof. Allgayer works at Mannheim Hospital, which is part of the University of Heidelberg, as well as at the German Cancer Research Centre (DKFZ). In October 2008, she received a research award from the Walter Schulz Foundation (along with a cheque for 25,000 euros) for her achievements in "essential molecular mechanisms of tumour progression, invasion and metastasis and minimal residual tumour diseases".

The Walter Schulz Foundation, which was established in 1980, mainly supports young scientists working in the field of tumour biology and immunology on projects that enable the more effective early diagnosis and therapy of tumour diseases. In addition, the foundation also provides hospitals and clinics with the money to purchase devices and equipment for the diagnosis and therapy of tumour diseases.

The urokinase system

A major objective of Allgayer’s work is to find specific biomarkers that enable the early identification of metastasis and the monitoring of treatment outcome. This means that she is looking for biomarkers that identify whether cancer treatment is successful and causes metastases to disappear or whether the patient becomes resistant to the drug used for treatment. Allgayer’s research focuses principally on the urokinase system that is overexpressed by many tumour cells (e.g., colon, stomach, breast and lung cancer) and which plays a major role in the cancer cells’ invasion of healthy tissue and their subsequent metastasis. The urokinase system consists of several components, including the enzyme urokinase, which was initially discovered in urine and subsequently in blood. Urokinase is a protease that converts biologically inactive plasminogen into active plasmin, which itself is an enzyme that activates other proteases that destroy components of the blood vessel walls and connective tissue. Urokinase is also known as u-type plasminogen activator (u-PA). It binds to the urokinase receptor (also known as urokinase-type plasminogen activator receptor or u-PAR), a glycoprotein consisting of three domains (D1-D3) which is anchored in the cell membrane by a glycosylphosphatidyl tail and which interacts with numerous different membrane proteins such as integrins (see diagram published in Nature Reviews Molecular Cell Biology 2002).

Urokinase system © Nature Reviews/Molecular Cell Biology 2002

The urokinase receptor u-PAR is overexpressed in many malignant (i.e. metastasising) tumours, for example colon, stomach, breast and lung cancer. The cancer cells carry a larger number of receptor molecules on the cell surface than cells found in healthy tissue that bind u-PA, which leads to the activation of an entire chain of enzymes that dissolve the structures of the surrounding tissue and enable the tumour cells to enter the tissue. In addition, the interaction with integrins and other molecules triggers signalling cascades inside the cell, which encourage the tumour cells to incessantly divide.

Clinical studies have provided evidence that the high activity of the urokinase system is an unfavourable prognosis factor for cancer patients. Allgayer and her team have shown that the u-PAR system is also found on individual tumour cells in the bone marrow of cancer patients. In such cases, the tumour cells appear to stay in a kind of inactive state until they are activated later, causing tumour recurrence or metastasis.

The determination of the urokinase system in solid tumours as well as individual tumour cells using molecular biology methods means that tumour recurrences can potentially be prevented in at-risk patients with an unfavourable prognosis if they are monitored closely and specific therapeutic measures are applied to improve their situation.

Erbitux infusion of Merck © Merck KG aA

In a recent paper published in Cancer Research 2009: 2461-70, Allgayer and her colleagues showed that u-PAR is an indicator for the effectiveness of the treatment of non-small cell lung cancer (NSCLC) with the antibody cetuximab. NSCLC cell lines that express large quantities of u-PAR were resistant to this drug. This result is of huge importance for Merck KGaA, which markets cetuximab under the brand name Erbitux and who have shown in a clinical Phase II study that Erbitux, which has been approved for the treatment of colon cancer, is also effectively prolonging the survival of patients with advanced NSCLC when combined with platinum-based chemotherapy.

Micro-RNAs as a measure of metastasis?

Allgayer and her team have discovered another type of molecule that promotes the spread of malignant tumours in the colon. A specific micro-RNA, miR-21, suppresses the production of the tumour suppressor protein Pdcd4, which prevents colon cells from becoming tumour cells and metastasising.

MicroRNAs are short DNA transcripts that serve as control elements for the type and quantity of proteins that are synthesised by the cell. They attach to mRNAs, thereby blocking them or initiating their degradation.

The risk of developing cancer increases if Pdcd4 disappears from the cells. In another study, the scientists from Heidelberg were able to show that the loss of Pdcd4 is associated with an increased risk of death in colon cancer patients. The study shows that high levels of miR-21 are present in colon cancer cells and that these trigger the invasion of cancer cells into healthy tissue. The researchers now hope that clinical studies will show whether an increase in the quantity of miRNA and the decrease of the tumour suppressor protein Pdcd4 are reliable molecular biomarkers for determining the degree of metastasis and would enable corresponding changes in patient treatment.

Professor Dr. Dr. Heike Allgayer studied medicine at the University of Munich before doing her doctorate at the Anderson Cancer Centre in Houston, Texas in the field of molecular biology. She specialised in surgery at the University of Munich Großhadern Hospital, habilitating in experimental surgery. She has been head of the Department of Experimental Surgery/Molecular Oncology at the Medical Faculty in Mannheim since 2004 and she is also head of the clinical cooperation unit ‘Molecular Oncology of Solid Tumours' at the DKFZ. She has published over 160 papers in renowned scientific journals, is a member of numerous international associations, including the American Association of Clinical Oncology (ASCO), the American Association of Cancer Research (AACR) and the European Association of Cancer Research (EACR). Prior to receiving the Walter Schulz Foundation award, Professor Allgayer had already been awarded 20 research prizes, including the science prize of the Alfried-Krupp-von-Bohlen-and-Halbach Foundation in 2005.

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/biomarkers-for-the-identification-of-metastases