Research into metastasis will bring about treatments to fight cancer

Metastasis is responsible for 90% of the deaths caused by cancer. However, among the multiple processes involved in tumour growth it is the most puzzling phenomenon. Metastasis is described as the capacity of primary tumours to release malignant cells towards distant organs and to generate new tumours, which finally become fatal. In the last five years, thanks to deep knowledge about primary tumours and the introduction of advanced bioimaging techniques, the most closely-guarded secrets of metastasis are starting to be disclosed. Cutting-edge research in this field is the focus of the VII Barcelona BioMed Conference, organized by the Institute for Research in Biomedicine (IRB Barcelona) and the BBVA Foundation. Entitled "Metastasis Gens and Functions" and held from Monday to Wednesday at the Institut d’Estudis Catalans, the conference brings together 23 scientists from European and North American institutes that head research into this key process in order to beat cancer.

"Current research into metastasis has allowed improvements in diagnosis and prediction; little by little we will provide efficient therapeutic applications to convert cancer from a fatal disease into a chronic disease, but there is still a long way to go", explains Joan Massagué, adjunct director of IRB Barcelona and Head of the Cancer Biology and Genetics Program at the Memorial Sloan Kettering Cancer Center of New York (U.S.). Massagué and the North American researcher Tyler Jacks, director of the Oncology Centre at the Massachusetts Institute of Technology –MIT- of Cambridge (U.S.), devised the conference.

The 23 invited speakers and the hundred participants attending the scientific sessions work in basic and clinical laboratories where they address the big questions that remain unanswered: which genes and functions are involved in metastasis? when, where and how do they do this? and finally, are they mediators and therefore valid therapeutic targets for treatment?

A complex process that is starting to be unravelled

Until relatively recently, these questions could not be addressed and in centuries of studies scientists advanced very little. However, in the last five years research has taken a dramatic turn. The main reasons for this change are a more detailed knowledge of the original tumours, new conceptual theories about metastasis and the availability of new techniques for bioimaging and gene expression. Tyler Jacks, one of the leading researchers in cancer modelling in the laboratory, explains that "we can now observe tumour progression in vivo, see how it spreads and the patterns that malignant cells follow". This, coupled with the possibility to observe the genes that are active in distinct stages of tumour progression, thanks to gene expression analysis, have allowed the identification of groups of genes and the functions that they activate to produce metastasis.

Basic and clinical researchers in the fight against cancer

The conference brings together experts working directly with patients and those working on basic research in the lab. "This direct relationship between diverse specialists is the key to speeding up the generation of new knowledge that will benefit the patient", says Massagué. One of the examples of this type of research, known as translational research, is performed by the scientist Josep Baselga, director of the Instituto de Investigación Oncológica de la Vall d’Hebron, an expert in breast cancer metastasis. Baselga and his team work on double foci: improving risk prediction in early stage breast cancer metastasis and, on the basis of results from basic research, testing new combinations of drugs that attack the functions related to tumour metastatic capacity. The final objectives of current research into metastasis are mainly to achieve new therapeutic agents and reuse already existing drugs to combat this process. "We have the technology to do it and we are now asking the right questions; the answers are being received because we have a much better understanding of each of the stages of tumour development", concludes Massagué.

CONTEXT

Metastasis, an evolutionary process

One of the conceptual frameworks introduced by the researcher Joan Massagué, and which has revolutionized the focus of studies, is based on Darwin and his theory of evolution. It is known that for cancer cells to undergo metastasis they must evade many rules and barriers that have become increasingly more sophisticated over hundreds of millions of years of organismal evolution. Therefore, scientists began to consider metastasis as a Darwinian evolutionary process, consisting of the selection of cancel cell lines that have accumulated a series of alterations that make them unique. These cells become genetically armed to overcome the defence mechanisms of the organism, until they acquire characteristics that allow them to thrive in an environment which would otherwise be extremely hostile for them.

Essential requirements for metastasis to occur

It has been demonstrated that the emergence and development of metastasis call for two essential requirements: one, the acquisition of advantageous genetic alterations by tumour cells, and two, the acquisition of compatibility in the tissues to be colonized, which favours the later invasion of these metastatic cells and therefore the spread of the tumour.

Stages of tumour development towards metastasis

The biological cascade of metastasis involves highly specific phases such as the loss of cell adhesion, the increase in motor and evasive capacity of tumour cells, entry into circulation, migration towards other tissues and finally colonization of a distant organ. Scientists have started to examine each of these processes and are slowly identifying the genes and molecular mechanisms and pathways that allow the progression of metastasis.

Initiation of the tumour: cell proliferation, evasion of cell death, genomic instability, evasion of immunity. Expansion: formation of capillaries, co-action of the microenvironment, invasion. Dissemination: intravasation, survival in circulation, adhesion to capillaries. Spread: extravasation, survival. Metastasis: reactivation, final colonization.

Some answers to critical questions

Promising results that contribute to our understanding of metastasis lead researchers to be optimistic. For example, recent studies indicate that certain cancer cells acquire the capacity to become metastatic when the tumour is still very small. Furthermore, there is new evidence on the complicity of healthy cells in the tissue to be colonized by tumour cells. These healthy cells not only help cancer cells to survive but also allow them to settle and dominate the organ. In addition, new data is available on the molecular mediators that allow tumour cells to enter and colonize specific organs. Finally, recent technological breakthroughs have allowed the validation of these new discoveries by means of the analysis of clinical samples from patients.

Examples of types and cancer and metastases

Distinct types of primary tumour differ in their capacity to colonize organs. For example, breast cancer metastasizes to bone, lung, brain and liver; lung cancer to liver, brains and bone; colon cancer to liver and lung; prostate cancer to bone; and sarcomas to lung.

Scientists work based on the hypothesis that cells invade one organ or the other depending on the compatibility between the tumour cells and the host organs. However, the molecular mechanisms that facilitate these compatibilities remain to be elucidated. Several results from Joan Massagué’s lab indicate that, for example, breast cancer cells that will metastasize to lung show distinct gene expression patterns to those that metastasize to bone. Scientists have also validated the gene expression in samples from patients and have established a causal relationship between the expression of certain genes and the appearance of breast cancer metastasis to lung. The discovery of the function of these genes has led to the realization of clinical trials using pharmacological inhibitors that act against the genes detected.