Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer

Abstract

Embryonic signalling pathways regulate progenitor cell fates in mammalian epithelial development and cancer. Prompted by the requirement for sonic hedgehog (Shh) signalling in lung development, we investigated a role for this pathway in regeneration and carcinogenesis of airway epithelium. Here we demonstrate extensive activation of the hedgehog (Hh) pathway within the airway epithelium during repair of acute airway injury. This mode of Hh signalling is characterized by the elaboration and reception of the Shh signal within the epithelial compartment, and immediately precedes neuroendocrine differentiation. We reveal a similar pattern of Hh signalling in airway development during normal differentiation of pulmonary neuroendocrine precursor cells, and in a subset of small-cell lung cancer (SCLC), a highly aggressive and frequently lethal human tumour with primitive neuroendocrine features. These tumours maintain their malignant phenotype in vitro and in vivo through ligand-dependent Hh pathway activation. We propose that some types of SCLC might recapitulate a critical, Hh-regulated event in airway epithelial differentiation. This requirement for Hh pathway activation identifies a common lethal malignancy that may respond to pharmacological blockade of the Hh signalling pathway.

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Unlike the situation in BCCs and meduloblastomas, gene mutation is not primarily responsible for activated Hh signaling in these tumors Watkins et al, 2003). There is evidence to indicate ligand-dependent growth in most extracutaneous cancers.…”

Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma

“…In addition to genetic alterations, ligand-dependent stimulation of Hh signaling has recently been shown to promote tumor cell growth in different types of human cancers (Berman et al, 2002Thayer et al, 2003;Watkins et al, 2003;Karhadkar et al, 2004;Scales and de Sauvage, 2009). In RMS, aberrant activation of the Hh cascade has been detected in primary specimens and has been attributed to genetic inactivation of Ptch1 or of suppressor of fused (SUFU), like Ptch1, a negative regulator of Hh signaling, or to Gli1 amplification (Roberts et al, 1989;Khatib et al, 1993;Ragazzini et al, 2004;Tostar et al, 2006;Oue et al, 2010).…”

Hedgehog Signaling Is Required for Effective Regeneration of Exocrine Pancreas

“…[10][11][12][13][14][15] Mature tissue homeostasis at these sites appears to be a consequence of Hh-mediated stem or progenitor cell self-renewal within the organspecific stem cell niche. In addition to this observed role in "baseline" states, more recent work suggests that the Hh pathway also plays a critical role in regenerative responses to tissue injury.…”