Smoothened and Patched and Sonic Hedgehogs – From Cyclopic Sheep to Targeted Basal Cell Carcinoma Treatment

By Simon Madorsky, MD | October 11, 2011

What does Frizzled, Frazzled, Dishevelled, and Smoothened have to do with the Sonic Hedgehog? These are some of the humorously named genes in Drosophila fruit flies that also happened to be expressed in humans. Besides adding character to the genes, these names occasionally reflect the traits they describe. Hedgehog (Hh) gene is part of the Hedgehog signalling pathway involved in cell growth and differentiation.

It was named Hedgehog, as the mutant fly larvae resembled a hedgehog. One of the human hedgehog genes was named Sonic Hedgehog (SHH), based on the Sega computer game character.

To complete the basic understanding of oncogenetics of basal cell carcinoma (BCCa), the function of two more genes needs to be understood – Patched (PTCH) and Smoothened (SMO).

Patched (PTCH) is a transmembrane protein receptor of the phospholipid bilayer (cell membrane) that binds and is acted on by Sonic Hedgehog (SHH) and, in turn, acts upon the Smoothened (SMO), another transmembrane protein and a signal transducer.

Without Sonic Hedgehog (SHH), Patched (PTCH) acts to inhibit Smoothened (SMO) signaling. With SHH bound to PTCH, SMO signaling is uninhibited and nuclear transcription occurs. The intermediary between SMO and transcription are the Gli signaling proteins.

The specific products of nuclear transcription are tumor promoting effects such as unregulated cell division, downregulated apoptosis (programmed cell death), factors that increase proliferation of fibroblasts (sclerosing BCCa), products such metalloproteinase (digests basement membrane), and extracellular mucin. The mesenchymal mucins, likely products of stromal cells, represent hyaluronic acid and dermatan sulfate. These provide some of the classic characteristics of nodular and superficial BCCa’s – translucence, pearlescent shine, and soft and mushy consistency. Thus, the tumors erode easily and respond to curettage.

The resulting cleft-like spaces often contain alcian blue-positive mesenchymal mucoid material. This mucin is easily washed out during histologic processing giving a characteristic microscopic appearance. The nodules of tumor show a peripheral palisade of basaloid cells and at their interface with the stroma, slit-like stromal retraction is seen with mucin deposition in the papillary dermis.

The slit-like retraction with mucin deposition in the adjacent stroma causes the nests of BCC to be only loosely adherent to the collagen. Thus, during processing, the tumor cell nests can drop out of the tissue sample, leaving nothing but an empty space, an important clue to BCC.

Several mutations in the Hedgehog Signalling Pathway have been implicated in tumorigenesis. In extensively studied autosomal dominant Nevus Basal Cell Syndrome (Gorlin syndrome), mutation of the Patched tumor suppressor gene disables it from binding to Smoothened which signals nuclear transcription and cell proliferation. Non-familial sporadic BCCa’s have been shown to have mutations in either Patched (PTCH) or Smoothened (SMO) genes in two-thirds of cases.

Targeted treament of the hedgehog pathway has focused on modulation of SMO. The most clinically advanced SMO targeting agents are cyclopamine-competitive. Cyclopamine was named for one-eyed lambs which were born to sheep which grazed on wild corn lily at a farm in Idaho. In 1957 the US Department of Agriculture started an eleven-year investigation which led to the identification of cyclopamine as the cause of the birth defect. This teratogen caused the development of cyclopia by inhibiting the hedgehog signaling pathway.

Vismodegib is the investigational drug derived at the crossroads of fruit fly genetics and cyclopic sheep. It acts as a cyclopamine-competitive antagonist of the Smoothened receptor (SMO). Vismodegib provided a “substantial clinical benefit” for patients with locally advanced and metastatic basal cell carcinoma in a phase II clinical trial. (Vismodegib Phase II trial update)

In addition to the Hedgehog pathway, a well known oncogene, p53 mutation, plays a role in pathogenesis of basal cell carcinoma. It has been documented in up to 40% of studied BCCa’s and is expressed preferentially in aggressive growth variants. 72% of the p53 mutations bear the signature of UV light induction.

As scientific discovery marches forward, US researchers have discovered yet another potential inhibitor of the Hedgehog signalling pathway which they have dubbed ‘robotnikinin’. The name was chosen in honor of Sonic Hedgehog’s nemesis – Dr. Robotnik.