ABSTRACT
Angiosarcoma/lymphangiosarcoma is a rare malignancy with poor prognosis. We generated a mouse model with inducible endothelial-cell-specific deletion of Tsc1 to examine mTORC1 signaling in lymphangiosarcoma. Tsc1 loss increased retinal angiogenesis in neonates and led to endothelial proliferative lesions from vascular malformations to vascular tumors in adult mice. Sustained mTORC1 signaling was required for lymphangiosarcoma development and maintenance. Increased VEGF expression in tumor cells was seen, and blocking autocrine VEGF signaling abolished vascular tumor development and growth. We also found significant correlations between mTORC1 activation and VEGF, HIF1α, and c-Myc expression in human angiosarcoma samples. These studies demonstrated critical mechanisms of aberrant mTORC1 activation in lymphangiosarcoma and validate the mice as a valuable model for further study.
Subject(s)
Autocrine Communication , Cell Transformation, Neoplastic/metabolism , Endothelial Cells/enzymology , Lymphangiosarcoma/metabolism , Multiprotein Complexes/metabolism , Neovascularization, Pathologic , TOR Serine-Threonine Kinases/metabolism , Vascular Endothelial Growth Factor A/metabolism , Angiogenesis Inhibitors/pharmacology , Animals , Autocrine Communication/drug effects , Cell Movement , Cell Proliferation , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Cells, Cultured , Endothelial Cells/drug effects , Endothelial Cells/pathology , Enzyme Activation , Genotype , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/analysis , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lymphangiosarcoma/drug therapy , Lymphangiosarcoma/genetics , Lymphangiosarcoma/pathology , Mechanistic Target of Rapamycin Complex 1 , Mice, Knockout , Mice, Nude , Multiprotein Complexes/antagonists & inhibitors , Neoplasm Invasiveness , Phenotype , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-myc/analysis , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , RNA Interference , Receptors, Vascular Endothelial Growth Factor/metabolism , Retinal Neovascularization/genetics , Retinal Neovascularization/metabolism , Retinal Neovascularization/pathology , Signal Transduction , TOR Serine-Threonine Kinases/antagonists & inhibitors , Transfection , Tuberous Sclerosis Complex 1 Protein , Tumor Burden , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Vascular Endothelial Growth Factor A/analysis , Vascular Endothelial Growth Factor A/antagonists & inhibitorsABSTRACT
The concept of "lymphangiosarcoma" remains obscure. Therefore, we reported a patient with lymphangiosarcoma, resistant to immunotherapy. The patient presented with impressive and discriminative features: clinically an ill-defined edematous lesion with lymphorrhea and pathologically atypical vascular channel formation without extravasation of blood, clearly distinguished from common angiosarcoma with hemorrhage. From this case, a lymphangiosarcoma cell line, MO-LAS, was established and its characteristics were compared with the hemangiosarcoma cell line, ISO-HAS. Flow cytometric analysis revealed that MO-LAS was negative for factor VIII-related antigen, but positive for CD31, D2-40, NZ-1, and vascular endothelial growth factor receptor-3 (VEGFR-3), similar to ISO-HAS. However, MO-LAS expressed a much higher level of homeobox gene PROX1, indicating a lymphatic phenotype, compared with ISO-HAS. Furthermore, MO-LAS showed a much lesser expression of oncogenes and much lower sensitivity against lymphokine-activated killer (LAK) cells. Lymphangiosarcoma may be difficult to recognize by the immune system. Conclusively, the establishment of MO-LAS, a novel angiosarcoma cell line bearing lymphatic characters, strongly suggests the entity of lymphangiosarcoma.
Subject(s)
Cell Line, Tumor , Lymphangiosarcoma/genetics , Lymphangiosarcoma/metabolism , Aged , Biopsy , Carcinogens , Cytotoxicity, Immunologic , Gene Expression , Hemangiosarcoma/genetics , Hemangiosarcoma/immunology , Hemangiosarcoma/metabolism , Hemangiosarcoma/pathology , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Immunophenotyping , Killer Cells, Lymphokine-Activated/immunology , Lymphangiosarcoma/immunology , Lymphangiosarcoma/pathology , Male , Phenotype , Skin/pathology , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
Hereditary lymphedemas that are not associated with other malformations usually affect the lower limbs and are inherited in an autosomal dominant fashion. These non-syndromic hereditary lymphedemas are categorized by their age of onset, being either congenital (Milroy disease) or having an onset in childhood or around puberty (Meige disease). We describe a family in which three individuals in three generations had unusually late onset of lymphedema in their mid-twenties or thirties. The proband additionally developed a very rare lymphangiosarcoma. This tumor, usually associated with post-mastectomy lymphedema, has not been described in late-onset hereditary lymphedema. Because of an unusually high incidence of multiple primary tumors in association with lymphangiosarcoma in the literature (approximately 10%) and the proband's own familial cancer background, we speculate that an inherited predisposition to malignancy may underlie the development of lymphedema-associated lymphangiosarcoma.
