[42] The Sonic Hedgehog Pathway in Chordoma

JM Cates, DM Itani, KC Homlar, SJ Olson, GE Holt, HS Schwartz, CM Coffin, BD Harfe. Vanderbilt University Medical Center, Nashville, TN; Vanderbilt Orthopaedic Institute, Nashville, TN; University of Florida, Gainesville, FL

Background: Chordomas are malignant primary bone tumors that show morphologic and molecular evidence of notochordal differentiation. Sonic hedgehog (SHH) is a crucial morphogen secreted by the fetal notochord that directs embryonic patterning of the neural tube and adjacent sclerotomes. In contrast to the early fetal notochord, putative intraosseous notochordal remnants recently identified in mice do not appear to express SHH. It is unknown whether the nucleus pulposus of the adult intervertebral disc (IVD), benign notochordal cell tumors (BNCT), or chordomas express SHH or the SHH receptor/signaling complex, patched (PTCH) and smoothened (SMO). However, genetic studies have documented gains of chromosome 7q36, which contains the SHH locus, in many chordomas.
Design: Archived chordal tissue samples were stained for SHH and PTCH by immunohistochemistry. Skull base chondrosarcomas were stained for comparison. SHH was considered positive if >10% cells showed cytoplasmic staining of at least moderate intensity. For PTCH, the presence of any specific cytoplasmic immunoreactivity was considered positive.
Results: SHH is expressed in human fetal notochord and chordomas of the sacrum (n=11), skull base (n=12), and mobile spine (n=4). In contrast to fetal notochord, PTCH is co-expressed in 92% of SHH-positive chordoma samples. Notably, the 2 BNCTs examined are negative for SHH and PTCH, as are most chondrosarcomas, IVDs, and the 1 dedifferentiated chordoma studied.

SHH and PTCH Expression in Chordal Tissues and Skull Base Chondrosarcoma

	n	SHH+	PTCH+
Conventional chordoma	23	22	20
Chondroid chordoma	4	4	4
Dedifferentiated chordoma	1	0	0
Benign notochordal cell tumor	2	0	0
Chondrosarcoma	6	1	1
Nucleus pulposus of IVD	7	1	0/3
Notochord	2	2	0

Conclusions: SHH and its cognate receptor PTCH are co-expressed in most chordomas. In contrast, this pathway does not appear active in human notochord (at the gestational ages examined), nucleus pulposus of the adult IVD, or in BNCT. SHH signaling is not activated in chondrosarcoma or in chordomas that have undergone dedifferentiation. Whether aberrant activation of this autocrine signaling pathway contributes to chordomagenesis should be investigated further in murine models and in putative precursor lesions of chordoma such as BNCT and notochordal rests.
Category: Bone & Soft Tissue

Tuesday, March 10, 2009 9:30 AM

Poster Session III # 14, Tuesday Morning