heparitin-sulfate and Sarcoma

Sarcomas comprise a heterogeneous group of rare malignancies of mesenchymal origin including more than 70 subtypes. They may arise in muscle, bone, cartilage and other connective tissues. Their high histological and genetic heterogeneity makes diagnosis and treatment very challenging. Deregulation of heparanase has been found in several sarcoma subtypes and high expression levels have been correlated with poor prognosis in Ewing's sarcoma and osteosarcoma. Altered expression of specific heparan sulfate proteoglycans and heparan sulfate biosynthetic enzymes has also been observed. Advances in molecular pathogenesis of sarcomas have evidenced the critical role of several heparan sulfate binding growth factors and receptor tyrosine kinases, highly interconnected with the microenvironment, in sustaining tumor growth and progression. Interference with heparanase/heparan sulfate functions represents a potential therapeutic approach in sarcoma. In this chapter, we summarize the current knowledge about the biological significance of heparanase expression and its potential as a therapeutic target in subtypes of both soft tissue and bone sarcomas. Particular emphasis is given to the involvement of heparan sulfate proteoglycans and their synthesizing and modifying enzymes in bone physiology and disorders leading up to the pathobiology of bone sarcomas. The chapter also describes the cooperation between exostin loss-of-function and heparanase upregulation in hereditary Multiple Osteochondroma syndrome as a paradigmatic example of constitutive alteration of the heparanase/heparan sulfate proteoglycan system which may contribute to progression to malignant secondary chondrosarcoma. Preclinical evidence of the role of heparanase as a promising therapeutic target in various sarcoma subtypes is finally resumed.

Topics: Glucuronidase; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Sarcoma

The heparan sulfate (HS) mimic/heparanase inhibitor roneparstat (SST0001) shows antitumor activity in preclinical sarcoma models. We hypothesized that this 100% N-acetylated and glycol-split heparin could interfere with the functions of several receptor tyrosine kinases (RTK) coexpressed in sarcomas and activated by heparin-binding growth factors. Using a phospho-proteomic approach, we investigated the drug effects on RTK activation in human cell lines representative of different sarcoma subtypes. Inhibition of FGF, IGF, ERBB and PDGF receptors by the drug was biochemically and functionally validated. Roneparstat counteracted the autocrine loop induced by the COL1A1/PDGFB fusion oncogene, expressed in a human dermatofibrosarcoma protuberans primary culture and in NIH3T3COL1A1/PDGFB transfectants, inhibiting cell anchorage-independent growth and invasion. In addition, roneparstat inhibited the activation of cell surface PDGFR and PDGFR-associated FAK, likely contributing to the reversion of NIH3T3COL1A1/PDGFB cell transformed and pro-invasive phenotype. Biochemical and histological/immunohistochemical ex vivo analyses confirmed a reduced activation of ERBB4, EGFR, INSR, IGF1R, associated with apoptosis induction and angiogenesis inhibition in a drug-treated Ewing's sarcoma family tumor xenograft. The combination of roneparstat with irinotecan significantly improved the antitumor effect against A204 rhabdoid xenografts resulting in a high rate of complete responses and cures. These findings reveal that roneparstat exerts a multi-target inhibition of RTKs relevant in the pathobiology of different sarcoma subtypes. These effects, likely cooperating with heparanase inhibition, contribute to the antitumor efficacy of the drug. The study supports heparanase/HS axis targeting as a valuable approach in combination therapies of different sarcoma subtypes providing a preclinical rationale for clinical investigation.

Topics: Animals; Biomimetic Materials; Cell Line, Tumor; Female; Heparin; Heparitin Sulfate; Humans; Mice; Mice, Nude; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Sarcoma; Signal Transduction; Xenograft Model Antitumor Assays

The distribution of basement membrane (BM) markers, type IV collagen, laminin (LM), heparan sulphate proteoglycan (HSP) and fibronectin (FN) has been studied by indirect immunofluorescence using specific antibodies, in tumoural pathology. The disrupted pattern of BM by these markers in severe dysplastic lesions of the breasts, the bronchi and uterine cervix provides evidence for malignancy. In invasive carcinomas, there is generally a loss of these BM components, with FN persisting in the stroma. The loss of these markers in BM is concomitant and superimposable in double staining studies. In embryonic tumours, the presence of BM markers is related to a mesenchymal differentiation of malignant cells with pericellular FN and/or maturation towards organoid structures with BM. In sarcomas, there is a loss of the pericellular BM staining around most transformed muscular and Schwann cells and adipocytes. The persistence of this labelling in some well-differentiated areas can help to diagnose the nature of the sarcoma. The persistence of intercellular filaments of FN corresponds to the mesenchymal and/or sarcomatous nature of undifferentiated anaplastic proliferations.

Topics: Basement Membrane; Breast Neoplasms; Cell Transformation, Neoplastic; Collagen; Female; Fibronectins; Fluorescent Antibody Technique; Heparitin Sulfate; Humans; Laminin; Lung Neoplasms; Male; Neoplasms; Neoplasms, Germ Cell and Embryonal; Sarcoma

Six cases of synovial sarcoma were examined histochemically in order to clarify the components of mucosubstances in the tumor tissues. The tumors were classified into 1) monophasic type, 2) predominantly monophasic type with focal biphasic differentiation, and 3) biphasic type. The former two groups and sarcomatous areas in the biphasic tumors contained various amounts of hyaluronic acid, chondroitin sulfate, and, in some cases, heparitin sulfate. By contrast, the epithelioid regions in the biphasic-type tumors had periodic acid-Schiff-positive glycoproteins which contained various amounts of sialic acid, in addition to hyaluronic acid and chondroitin sulfate. The significance of the presence of glycoproteins in the mesenchymal tumors is emphasized. It seems likely that the synovial sarcomas contain various kinds of mucosubstances and that sensitivity to hyaluronidase treatment is not necessarily the diagnostic criterion of synovial sarcoma.

Topics: Adult; Chondroitin Sulfates; Female; Glycoproteins; Heparitin Sulfate; Histocytochemistry; Humans; Hyaluronic Acid; Male; Middle Aged; Mucous Membrane; N-Acetylneuraminic Acid; Sarcoma; Sialic Acids; Staining and Labeling; Synovial Membrane

The distribution of four basement membrane components, type IV collagen (C IV), laminin (LM), heparan sulfate proteoglycan (HSP) and fibronection (FN) has been studied by indirect immunofluorescence using specific antibodies, in benign and malignant proliferations of the mammary gland and in soft tissue tumors. In breast carcinomas, specially intraductal cancers, there is a progressive and concomitant loss of these macromolecules around tumoral cells, preceding an overt tumoral invasion. In sarcomas, FN is frequently seen between malignant cells but the regular pericellular labeling observed around normal muscular cells, Schwann cells and adipocytes is absent. Nevertheless, the persistance of some pericellular staining with anti-C IV, anti-LM, anti-HSP and anti-FN antisera, in most differentiated territories of liposarcomas, leiomyosarcomas and neurifibrosarcomas can help to the diagnosis of such lesions.

Topics: Basement Membrane; Breast Neoplasms; Collagen; Female; Fibronectins; Fluorescent Antibody Technique; Heparitin Sulfate; Humans; Laminin; Neoplasms; Sarcoma

Using a modified papain digestion cetylpyridinium salt precipitation method, glycosaminoglycans were isolated from 21 mesotheliomas, 34 primary lung carcinomas, 12 carcinomas of other sites, and 7 soft tissue sarcomas. Qualitatively, hyaluronic acid (HA) was present in 20 of 21 mesotheliomas, about half of the primary lung adenocarcinomas, and all of the soft tissue sarcomas. On the average, HA constituted 45% of the total glycosaminoglycans in the mesotheliomas and 28% of the total in the lung cancers. Quantitatively, mesotheliomas contained statistically greater amounts (mean value, 0.74 mg/g) of HA than primary lung adenocarcinomas (mean value, 0.08 mg/g), but were not statistically different from soft tissue sarcomas (mean value, 2.01 mg/g) or primary ovarian serous neoplasms (mean value, 0.92 mg/g). The study concludes that, contrary to previous reports, HA is neither the sole nor the predominant glycosaminoglycan in most mesotheliomas, but, given the proper clinical and histologic setting, the finding of sufficiently high levels (greater than 0.4 mg/g dry tissue extract) supports the diagnosis of mesothelioma when the alternative diagnosis is primary adenocarcinoma of lung.

Topics: Adenocarcinoma; Carcinoma; Chondroitin Sulfates; Dermatan Sulfate; Diagnosis, Differential; Electrophoresis, Cellulose Acetate; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Lung Neoplasms; Mesothelioma; Ovarian Neoplasms; Sarcoma