Hedgehog Signal Inhibition Hope or Hype?

Julie E. Bauman, MD, and Dennie V. Jones, Jr, M
Published: Wednesday, May 19, 2010
Once a human malignancy metastasizes, currently available cytotoxic chemotherapy is usually palliative. While conventional chemotherapy regimens are associated with objective tumor regression, this only occurs in a minority of patients. Transient disease stabilization is common, but disease progression and ultimately death secondary to malignancy are expected. In most malignancies, conventional chemotherapy has reached a plateau in terms of response rate, progression-free survival, and most important, overall survival. While modest gains in response rate are achieved by combining a greater number of cytotoxic agents, increased toxicity is seen without improvement in survival. Recent discoveries in cellular and tumor biology have led to the development of novel targeted therapies that hold the promise of more selective anticancer treatment. One such molecular target is the Hedgehog signal transduction network.

The Hedgehog signal transduction pathway is named after a gene discovered by 1995 Nobel laureates Edward B. Lewis and Christiane Nüsslein- Volhard, who were screening for developmental genes causing body segmentation in Drosophila melanogaster (fruit fly). An experimental mutation in the Hedgehog gene caused fruit flies to develop as spikey balls reminiscent of a hedgehog, rather than with classic anterior-posterior segmentation. The Hedgehog signaling pathway plays a critical role in embryonic development, differentiation, and tissue polarity. Aberrant activation of this pathway occurs frequently in human cancer, whereas inactivation is associated with developmental disorders.

Examining Hedgehog Signaling

Hedgehog signaling is initiated by the binding of Hedgehog ligand to Patched, a 12-transmembrane protein receptor. This ligand-receptor family includes three known ligands, Sonic Hedgehog, Indian Hedgehog, and Desert Hedgehog, and two highly homologous receptors, Patched1 and Patched2. The Hedgehog pathway is repressed under normal conditions. In the absence of Hedgehog ligand, Patched constitutively inhibits Smoothened, a 7-transmembrane protein receptor that is a key downstream mediator of Hedgehog signaling. Downstream of Smoothened are the effector molecules of Hedgehog signaling: the Gli proteins (Gli1, Gli2, and Gli3), which function as zinc finger activators, repressors of transcription, or both. When Smoothened is inhibited, the Gli proteins are sequestered in the cytoplasm and bound to microtubules in a complex with the Fused (Fu) and Suppressor of Fused (SuFu) proteins; however, when Hedgehog binds Patched, the inhibition of Smoothened is relieved and the Gli proteins are released to enter the nucleus and induce transcription of Hedgehog target genes. There are a variety of downstream protein targets of Hedgehog signaling, including cyclins B1 and D1, p21, BCL-2, IL1R, and p53; these proteins are associated with mitosis, apoptosis, or resistance to therapy.

Implications of Patched Gene Mutations

Considerable additional insight into the role of the Hedgehog pathway in vertebrate development and human cancers has come from the discovery that mutations of the Patched gene are associated with a rare hereditary form of basal cell carcinoma (BCC): the Gorlin syndrome, also known as the basal cell nevus syndrome.1,2 The most common manifestation of this disorder is the early development of multiple BCCs, usually on sun-exposed areas. Affected persons are also at risk for medulloblastomas, usually by age 3; palmar and/or plantar cutaneous pits; odontogenic cysts and other skeletal abnormalities; genitourinary anomalies, usually calcified ovarian fibromas; and a predisposition to unusual neoplasms such as sarcomas, cardiac fi bromas, and meningiomas.3-6 Most germline mutations of Patched1 are loss- of-function nonsense mutations that lead to a constitutive activation of Smoothened. In sporadic BCCs, one copy of the Patched gene is frequently absent (loss of heterozygosity), while the other copy contains mutations, most of which are predicted to interrupt the function of Patched1.

Mice that are heterozygous for the Patched1 null mutation exhibit a phenotype that resembles the basal cell nevus syndrome, including the development of BCCs, medulloblastomas, and rhabdomyosarcomas. These observations indicate that Patched may function as a tumor suppressor. Activation of the Hedgehog signal transduction pathway due to loss-of-function mutations of Patched1 in human BCCs disrupts his feedback regulation, leading to uncontrolled Smoothened signaling. Activating mutations of Smoothened, on the other hand, are resistant to Patched1–mediated inhibition, which leads to an outcome similar to Patched1 inactivation. Endogenous activation of the Hedgehog pathway, through loss-of-function mutations of Patched, gain-of-function mutations of Smoothened, or loss-of-function of SuFu, is found in BCCs, trichoepitheliomas, medulloblastomas, and subsets of prostate cancer.

Hedgehog Pathway’s Role in Cancer

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