photo: IMM site

The Angiogenesis of the Institute of Molecular Medicine (IMM) aims to develop scientific knowledge that allows limiting or encouraging the formation of new blood vessels, thus proposing innovative therapeutic strategies in diseases related to excessive growth of blood vessels, such as cancer, or in diseases related to vascular insufficiency, such as peripheral arterial disease.

Angiogenesis is the process of formation and growth of new blood vessels from pre-existing ones. Under physiological conditions, it is critical in embryonic development, tissue growth, ovulation, in the formation of corpus luteum, and in healing and regeneration. This process is regulated by proangiogenic and antiangiogenic factors, which, in normal situations, are in a dynamic equilibrium in adults. Disturbances in this balance lead to the growth or regression of existing vessels and may contribute to the development of various diseases. Accordingly, pathologic angiogenesis is characterized by excessive or inefficient neovascularization. Therefore, therapeutic strategies that interfere with the formation of vasculature are considered of utmost importance in clinical practice.

The idea that tumour progression depended on neovascularization began in the 1960s. Some experiments demonstrated that the survival of tumour cells of solid tumours were not possible beyond a 2-3 mm diameter if not accompanied by the formation of new vessels. Up to that diameter, tumours receive oxygen and nutrients by simple diffusion, not requiring irrigation by own blood vessels. beyond this size, in the absence of newly formed vasculature, the tumour stops growing and cell death occurs.

In 1971, researcher Judah Folkman, considered the “father” of tumour angiogenesis, published an article in the New England Journal of Medicine on the need that tumours have to induce angiogenesis in order to obtain the oxygen and nutrients that allow them to grow and spread in the body. Thus, Folkman proposed that tumour growth and the formation of metastases are angiogenesis dependent, and that blocking it was an effective strategy to stop tumour growth and treat cancer.

Since 1971, many researchers have devoted themselves to understanding the molecular and cell mechanisms that regulate the angiogenesis process. This knowledge has led to angiogenic inhibitors being used in preclinical and clinical trials with the purpose of revolutionising clinical oncology and are now widely used in the treatment of cancer by eradicating tumour vasculature.

Today, clinical experience has demonstrated that antiangiogenic therapy prolongs the life of some cancer patients but only by months, without resulting in cure. Some fundamental research works have even alerted to the fact that those therapies, which are effective in the treatment of primary tumours, may even promote the formation of metastases. Science has, pertinently, raised many questions regarding the use of antiangiogenic agents in cancer treatment.

Therefore, it is up to us to take advantage of all existing knowledge in order to contribute in innovative ways to the development of new knowledge that may be relevant in the treatment of cancer.

We have demonstrated recently that low doses of ionising radiation promote angiogenesis and through this process we found that there could be greater tumour progression and the formation of metastases. Different animal and in vitro models were used in this work.

In order to understand the relevance of the results obtained, it is important to comprehend what these low doses of ionizing radiation are. During radiotherapy, which is one of the most used forms of cancer treatment, in order to have a tumour volume to be exposed to a daily dose of ionizing radiation that will contribute to cell death, the healthy tissue surrounding the tumour will also need to be exposed to ionizing radiation in doses that are lower than therapeutic ones. Thus, when developing dosimetric planning specific for each patient, one of the goals is to achieve the best compromise between the therapeutic dose that the tumour volume will need to be exposed to, and the low doses of ionising radiation that the healthy tissues will also need to be exposed to, with these low doses having no toxicity, or the lowest possible toxicity.

Our research focused precisely on this radiation low doses, and we found that doses below 0.8Gy promote angiogenesis, inducing the expression of proangiogenic factors and activating a few of its receptors on endothelial cells. Thus, this work proposes, for the first time, a new mechanism that may be extremely important to understand the pro-metastatic effects of ionizing radiation, as well as tumour recurrence following radiotherapy.

This work was only possible thanks to the strong collaboration between the Angiogenesis Unit and the Radiotherapy Service of Santa Maria Hospital (HSM). When speaking of this Service we refer to its director, Professor Isabel Monteiro Grillo, to the Medical Physics Unit and the entire technical team, acknowledging the commitment of all as being crucial to ensure accuracy in results.

It is now paramount to validate results in humans. To this effect, we are now studying the expression of important angiogenic factors in endothelial cells removed from the tissue of patients with rectal cancer who have undergone preoperative radiotherapy, with their informed consent. Three types of tissues will be collected during the surgery in accordance with the dose they have been exposed to, and by means of laser microdissection microscopy, our research will focus on the endothelial cells. Until samples arrive at our laboratory, the prior work of several members of staff is crucial, and I stress, at the Radiotherapy Service, the work of Professor Isabel Monteiro Grillo and of Doctors Filomena Pina and Esmeralda Poli; at the Surgery Unit, the work of Professor Henrique Bicha Castelo and Doctor João Malaquias; and in the Pathological Anatomy Department, that of Doctors Madalena Ramos, Emília Vitorino and Pedro Rodrigues.

We are confident that the results we will obtain in the course of this project will be highly relevant as, for the first time, the effect of low doses of ionising radiation, which are always present in radiotherapy, on vasculature and in the angiogenesis process, will be described. This knowledge will be of utmost importance for medical oncology in order to ascertain the relevance of these low doses in tumour recurrence or metastasis after radiotherapy. Knowledge of the underlying molecular and cell mechanisms will also enable the further optimisation of oncological protocols.

Once we have shown that certain doses of ionising radiation are proangiogenic, our goal is also to understand its contribution to therapeutic angiogenesis. Accordingly, we developed a model of lower limb ischemia in mice and we propose to investigate whether we can propose the use of low doses as a new therapeutic strategy to promote neovascularisation in ischemic diseases.

As a professor of the Faculty of Medicine of the University of Lisbon (FMUL) and director of a research unit of the IMM that works with the Clinical Services of the HSM on a daily basis, I recognize that the Academic Medical Centre of Lisbon (CAML) is indispensable to what we do and how we do it.

At our research unit, master and doctoral students, as well as postdoctoral researchers contribute to the scientific findings. It is a multidisciplinary team that includes biologists, biochemists and doctors, all with different visions and ways of acting when faced with a scientific challenge, and this fact fosters dynamic discussions. The daily collaboration with the Clinical Services of the HSM ensures that our work develops in order to meet the goal of making our scientific results relevant for human health and that it can be applied to the treatment of diseases that still pose a challenge to medicine.

Susana Constantino
Director of the Angiogenesis Unit, IMM-FMUL
Teacher, FMUL