'The Hallmarks of Cancer' is a seminal peer-reviewed article published in the journal Cell in January 2000 by the cancer researchers Douglas Hanahan and Robert Weinberg. The authors believe that the complexity of cancer can be reduced to a small number of underlying principles. The paper argues that all cancers share six common traits ('hallmarks') that govern the transformation of normal cells to cancer (malignant or tumor) cells. The traits ('hallmarks') that the authors highlight in the paper are (1) Cancer cells stimulate their own growth (self-sufficiency in growth signals); (2) They resist inhibitory signals that might otherwise stop their growth (insensitivity to anti-growth signals); (3) They resist their programmed cell death (evading apoptosis); (4) They can multiply indefinitely (limitless replicative potential) (5) They stimulate the growth of blood vessels to supply nutrients to tumors (sustained angiogenesis); (6) They invade local tissue and spread to distant sites (tissue invasion and metastasis). By November 2010, the paper had been referenced over 15,000 times by other research papers, and was downloaded 20,000 times a year between 2004 and 2007. As of March 2011, it was Cell's most cited article. In an update published in 2011 ('Hallmarks of cancer: the next generation'), Weinberg and Hanahan proposed two new hallmarks: (1) abnormal metabolic pathways, (2) evading the immune system and two enabling characteristics: (1) genome instability, and (2) inflammation. Cancer cells have defects in the control mechanisms that govern how often they divide, and in the feedback systems that regulate these control mechanisms (i.e. defects in homeostasis).