Narrow Results

Cancer can be viewed as a "tissue", where neoplastic cells are immersed into a peculiar microenvironment (the "tumor microenvironment", TME) which modulates tumor cell behaviour during multistep tumorigenesis. Based on this concept, antineoplastic therapy should be tuned to target not only tumor cells but also the cellular constituents of the TME. Such necessity is well exemplified by considering tumor angiogenesis, a major aspect of cancer biology.

Ion channels and transporters are increasingly recognized as relevant players in the tumor cell-TME cross-talk. For example, during tumor neo-angiogenesis, soluble factors as well as fixed components of the extracellular matrix (ECM) and membrane proteins determine signal exchange between the TME and the implicated cell types. The signalling network is coordinated by functional "hubs", which may be constituted by integrin receptors associated with other proteins to form macromolecular signalling platforms at the adhesive sites. These complexes often include ion channels.

The K⁺ channels encoded by the human ether-à-go-go related gene (Kv11.1, or hERG1) are frequently overexpressed in human cancers and regulate intracellular signalling by physically associating with integrin subunits and growth factor/chemokine receptors. In colorectal cancer (CRC) we recently identified a novel signalling pathway centered on hERG1 channels and integrins. This pathway involves the p53 protein, which is encoded by a tumor suppressor gene often mutated in human cancers. p53 controls angiogenesis, through a mechanism regulated by hERG1 K⁺ channels. The central role played by hERG1 in CRC angiogenesis suggests that targeting hERG1 may be an effective therapeutic option in patients with advanced CRC.

To better understand the above process, it is necessary to study the interlaced dynamics of the key microscopic actors by using dedicated mathematical models. We here review a simple model, of reductionist inspiration, that explores the intimate connections between apoptosis and hypoxia, passing through angiogenesis. We show that a dynamical switch takes place between the normoxia and cellular death conditions. When oxygen lacks, cells can cross the transition line and so gain their way towards the normoxia regime, by implementing point mutations that affect the p53 production and activation rate, with the involvement of K⁺ ion homeostasis, in agreement with the experimental observations.

There exist many reviews on the biological and biochemical interactions of cancer cells and endothelial cells during the transmigration and tissue invasion of cancer cells. For the malignant progression of cancer, the ability to metastasize is a prerequisite. In particular, this means that certain cancer cells possess the property to migrate through the endothelial lining into blood or lymph vessels, and are possibly able to transmigrate through the endothelial lining into the connective tissue and follow up their invasion path in the targeted tissue. On the molecular and biochemical level the transmigration and invasion steps are well-defined, but these signal transduction pathways are not yet clear and less understood in regards to the biophysical aspects of these processes.

To functionally characterize the malignant transformation of neoplasms and subsequently reveal the underlying pathway(s) and cellular properties, which help cancer cells to facilitate cancer progression, the biomechanical properties of cancer cells and their microenvironment come into focus in the physics-of-cancer driven view on the metastasis process of cancers. Hallmarks for cancer progression have been proposed, but they still lack the inclusion of specific biomechanical properties of cancer cells and interacting surrounding endothelial cells of blood or lymph vessels. As a cancer cell is embedded in a special environment, the mechanical properties of the extracellular matrix also cannot be neglected. Therefore, in this review it is proposed that a novel hallmark of cancer that is still elusive in classical tumor biological reviews should be included, dealing with the aspect of physics in cancer disease such as the natural selection of an aggressive (highly invasive) subtype of cancer cells displaying a certain adhesion or chemokine receptor on their cell surface.

Today, the physical aspects can be analyzed by using state-of-the-art biophysical methods. Thus, this review will present current cancer research in a different light from a physical point of view with respect to cancer cell mechanics and the special and unique role of the endothelium on cancer cell invasion.

The physical view on cancer disease may lead to novel insights into cancer disease and will help to overcome the classical views on cancer. In addition, in this review it will be discussed how physics of cancer can help to reveal and propose the functional mechanism which cancer cells use to invade connective tissue and transmigrate through the endothelium to finally metastasize.

Finally, in this review it will be demonstrated how biophysical measurements can be combined with classical analysis approaches of tumor biology. The insights into physical interactions between cancer cells, the endothelium and the microenvironment may help to answer some "old," but still important questions in cancer disease progression.