muramidase and Leiomyosarcoma

A fraction of gastrointestinal stromal tumor (GIST) cells overexpress the platelet-derived growth factor receptor (PDGFR)A, although most overexpress KIT. It is not known if this is because these receptor tyrosine kinases have complementary oncogenic potential, or because of heterogeneity in the cellular origin of GIST. Little also is known about why Hedgehog (HH) signaling is activated in some GIST. HH binds to and inactivates the receptor protein patched homolog (PTCH).. Ptch was conditionally inactivated in mice (to achieve constitutive HH signaling) using a Cre recombinase regulated by the lysozyme M promoter. Cre-expressing cells were traced using R26R-LacZ reporter mice. Tumors were characterized by in situ hybridization, immunohistochemistry, immunoblot, and quantitative reverse-transcriptase polymerase chain reaction analyses. Cell transformation was assessed by soft agar assay.. Loss of Ptch from lysozyme M-expressing cells resulted in the development of tumors of GIST-like localization and histology; these were reduced when mice were given imatinib, a drug that targets KIT and PDGFRA. The Hh signaling pathway was activated in the tumor cells, and Pdgfrα, but not Kit, was overexpressed and activated. Lineage tracing revealed that Cre-expressing intestinal cells were Kit-negative. These cells sometimes expressed Pdgfrα and were located near Kit-positive interstitial cells of Cajal. In contrast to KIT, activation of PDGFRA increased anchorage-independent proliferation and was required for tumor formation in mice by cells with activated HH signaling.. Inactivation of Ptch in mice leads to formation of GIST-like tumors that express Pdgfrα, but not Kit. Activation of Pdgfrα signaling appears to facilitate tumorigenesis.

Topics: Animals; Benzamides; Cell Transformation, Neoplastic; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Gene Expression; Genotype; Hedgehog Proteins; Humans; Imatinib Mesylate; Integrases; Intestinal Mucosa; Kruppel-Like Transcription Factors; Leiomyosarcoma; Mice; Muramidase; Nerve Tissue Proteins; Patched Receptors; Patched-1 Receptor; Piperazines; Promoter Regions, Genetic; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyrimidines; Receptor, Platelet-Derived Growth Factor alpha; Receptors, Cell Surface; Signal Transduction; Zinc Finger Protein GLI1; Zinc Finger Protein Gli2; Zinc Finger Protein Gli3

Primary leiomyosarcoma of bone is extremely rare. A 60-year-old woman had a mass in the right femur that was studied immunohistochemically and by electron microscopy. Human smooth-muscle actomyosin was detected in tumor cells, but human skeletal-muscle myoglobin and lysozyme (muramidase) were not. Electron microscopy of the tumor showed findings suggestive of a smooth-muscle origin, such as myofilaments, dense bodies, pinocytotic vesicles, and basement membrane. The results were diagnostic of leiomyosarcoma rather than rhabdomyosarcoma, fibrosarcoma, or malignant fibrous histiocytoma, which are similar neoplasms. We believe that ours is the first case of primary leiomyosarcoma of the bone proved by immunohistochemistry.

Topics: Actomyosin; Bone Neoplasms; Female; Femoral Fractures; Hip Prosthesis; Histocytochemistry; Humans; Immunochemistry; Leiomyosarcoma; Middle Aged; Muramidase; Myoglobin; Urinary Bladder Neoplasms