NOTCH1 and neoplasm: For instance, NICD physically cooperates with a major component of canonical WNT signaling, β-catenin[26], Smad tumor suppressor proteins[27], and the key regulators of cellular response to changes in oxygen concentration, such as hypoxia-inducible factor 1 alpha (HIF-1α)[28], thus obtaining direct crosstalk between Notch and the wingless/integrated (WNT), transforming growth factor-beta (TGF-β), and hypoxia-dependent signaling pathways.