Tissue architectural cues drive organ targeting of human tumor cells in zebrafish

ABSTRACTSites of metastasis are non-random, with certain types of cancers showing organ preference during distal colonization. Using multiple brain- and bone marrow-seeking human and murine breast cancer subclones, we determined that tumor cells that home to specific murine organs (brain and bone marrow) ultimately colonized analogous tissues (brain and caudal vein plexus [CVP]) in larval zebrafish. We then exploited the zebrafish model to delineate factors leading to differential cell homing and extravasation. Bone marrow-tropic clones showed higher expression of integrins and focal adhesions associated with mechanosensing machinery than brain-tropic clones and were more sensitive to vessel topography during extravasation. Knockdown of β1 integrin reduced extravasation and redistributed organ targeting from disordered vessels in the CVP to the brain. Our results show that organ selectivity is driven by topography- and cell type-dependent extravasation at the tumor-endothelial interface in the larval zebrafish and provide important insights into the early stages of metastasis.

At the heart of tissue: endothelin system and end-organ damage

ET (endothelin)-1 was first described as a potent vasoconstrictor. Since then, many other deleterious properties mediated via its two receptors, ETA and ETB, have been described, such as inflammation, fibrosis and hyperplasia. These effects, combined with a wide tissue distribution of the ET system, its up-regulation in pathological situations and a local autocrine/paracrine activity due to a high tissue receptor binding, make the tissue ET system a key local player in end-organ damage. Furthermore, ET-1 interacts in tissues with other systems such as the RAAS (renin–angiotensin–aldosterone system) to exert its effects. In numerous genetically modified animal models, non-specific or organ-targeted ET-1 overexpression causes intense organ damage, especially hypertrophy and fibrosis, in the absence of haemodynamic changes, confirming a local activity of the ET system. ET receptor antagonists have been shown to prevent and sometimes reverse these tissue alterations in an organ-specific manner, leading to long-term benefits and an improvement in survival in different animal models. Potential for such benefits going beyond a pure haemodynamic effect have also been suggested by clinical trial results in which ET receptor antagonism decreased the occurrence of new digital ulcers in patients with systemic sclerosis and delayed the time to clinical worsening in patients with PAH (pulmonary arterial hypertension). The tissue ET system allows therapeutic interventions to provide organ selectivity and beneficial effects in diseases associated with tissue inflammation, hypertrophy or fibrosis.

Management of Overactive Bladder

At least 80% of urology patients are taking several medications for any variety of other medical conditions. However, regarding treatment of overactive bladder (OAB) specifically, there are several antimuscarinic drugs available. Tolterodine and trospium chloride are, in essence, nonspecific in terms of muscarinic receptor selectivity. Solifenacin and oxybutynin show selectivity for the M1, and darifenacin is significantly M3 receptor specific (Slide 17).The potential benefit for selective antimuscarinic agents is that they might target the bladder more specifically and avoid anticholinergic side effects in other organ systems, specifically the brain and heart. We do know that M3 receptors are also present in the intestines and in the salivary glands; thus, we might not expect organ selectivity with an M3-specific receptor because that receptor would also potentially affect the salivary gland and the intestinal tract as well.There is a growing body of data regarding M3 activity specificity and decreased cognitive impairment in patients of various ages. This, as well as the reduction of cardiac side effects, are the major benefits of using an M3-selective anticholinergic medication rather than a nonselective agent for the treatment of OAB.