title: The vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy.
abstract: In this review, we address clinical aspects and mechanisms of ventricular dysfunction induced by anticancer drugs targeted to the ErbB2 receptor. ErbB2 antagonists prolong survival in cancer, but also interfere with homeostatic processes in the heart. ErbB2 is a coreceptor for ErbB4, which is activated by neuregulin-1. This epidermal growth factor-like growth factor is released from endothelial cells in the endocardium and in the myocardial microcirculation, hence contributing to intercellular crosstalk in the ventricle. We look at the physiological aspects of neuregulin-1/ErbB signaling in the ventricle, and review its (mal)adaptive responses in chronic heart failure. We also compare structural aspects of ErbB receptor activation in cancer and cardiac cells, and analyze the mode of action of current ErbB2 antagonists. This allows us to predict how these drugs interfere with paracrine processes in the ventricle. Differences in the mode of action of individual ErbB2 antagonists affect their impact on the function of the ventricle, considered to be "on-target" or "off-target." Establishing the relation between the cardiac side effects of ErbB2 antagonists and their impact on paracrine ventricular control mechanisms may direct the design of a next generation of ErbB2 inhibitors. For cardiologists, there are lessons to be learned from the unexpected side effects of ErbB2-targeted cancer therapy. The vulnerability of the heart as a pluricellular paracrine system appears greater than anticipated and intercellular crosstalk an essential component of its functional and structural integrity.
authors.affiliation: Laboratory of Physiology, University of Antwerp, Antwerp, Belgium. gilles.dekeulenaer@ua.ac.be
authors.forename: Gilles W
authors.initials: GW
authors.lastname: De Keulenaer
authors.forename: Kris
authors.initials: K
authors.lastname: Doggen
authors.forename: Katrien
authors.initials: K
authors.lastname: Lemmens
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D054715:Cardiotoxins / Q000009:adverse effects* / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000009:adverse effects*; D004699:Endocardium / Q000201:enzymology; D042783:Endothelial Cells / Q000201:enzymology*; D066246:ErbB Receptors / Q000378:metabolism; D006333:Heart Failure / Q000139:chemically induced* / Q000201:enzymology*; D006352:Heart Ventricles / Q000201:enzymology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D020890:Neuregulin-1 / Q000378:metabolism*; D019899:Paracrine Communication / Q000187:drug effects*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D054715:Cardiotoxins; D066246:ErbB Receptors; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; C094131:NRG1 protein, human; C508053:ERBB2 protein, human; C587689:ERBB4 protein, human