Expression of hyaluronan in normal and dysplastic bronchial epithelium and in squamous cell carcinoma of the lung.
ABSTRACT A series of 85 lung/bronchial tissue samples from 76 patients consisting of normal, metaplastic and dysplastic epithelium and different types of lung carcinomas were analyzed for the distribution of hyaluronan (HA), using a biotinylated hyaluronan binding complex as an HA-specific probe. The normal pseudo-stratified columnar bronchial epithelium was either negative for HA or displayed a weak staining around the basal cells. The epithelia of serous and mucous bronchial glands were HA negative whereas the submucosal connective tissue was strongly positive. In metaplastic, dysplastic and carcinoma in situ lesions the whole epithelium from basal to uppermost cells expressed HA on plasma membranes. Epithelial HA was also found in squamous cell carcinomas, but not in adenocarcinomas, carcinoid tumors or small cell carcinomas of the lung. Whereas epithelial HA was present in all lesions of the squamous cell type, the staining intensity displayed great local variability in 50% of the cases with severe dysplasia, carcinoma in situ and squamous cell carcinomas. In squamous cell carcinomas, such an irregular staining pattern was significantly associated with poor differentiation. Our results indicate that the expression of HA in different bronchial lesions and lung tumors is restricted to those showing squamous cell differentiation, being absent from other types of lung carcinomas. The increase of HA depleted areas in poorly differentiated squamous cell carcinomas emphasizes the important role of HA in tumor differentiation. HA on carcinoma cell surface may influence tumor growth and metastatic behavior.
- SourceAvailable from: Naoki Ishiguro[show abstract] [hide abstract]
ABSTRACT: Hyaluronan (HA) plays crucial roles in the tumourigenicity of many types of malignant tumours. 4-Methylumbelliferone (MU) is an inhibitor of HA synthesis. Several studies have shown its inhibitory effects on malignant tumours; however, none have focused on its effects on osteosarcoma. We investigated the effects of MU on HA accumulation and tumourigenicity of highly metastatic murine osteosarcoma cells (LM8) that have HA-rich cell-associated matrix, and human osteosarcoma cell lines (MG-63 and HOS). In vitro, MU inhibited HA retention, thereby reducing the formation of functional cell-associated matrices, and also inhibited cell proliferation, migration, and invasion. Akt phosphorylation was suppressed by MU (1.0 mM). In vivo, although MU showed only a mild inhibitory effect on the growth of the primary tumour, it markedly inhibited (75% reduction) the development of lung metastasis. Hyaluronan retention in the periphery of the primary tumour was markedly suppressed by MU. These findings suggested that MU suppressed HA retention and cell-associated matrix formation in osteosarcoma cells, resulting in a reduction of tumourigenicity, including lung metastasis. 4-Methylumbelliferone is a promising therapeutic agent targeting both primary tumours and distant metastasis of osteosarcoma, possibly via suppression of HA retention.British Journal of Cancer 11/2011; 105(12):1839-49. · 5.08 Impact Factor
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ABSTRACT: Hyaluronan is known to have pivotal roles in the growth, migration and invasion of malignant tumors. Bone metastases are critical lesions greatly impairing the quality of patients with malignancies. We investigated whether hyaluronan synthesis inhibitor supplements the inhibitory effects of zoledronic acid, which is a conventional therapeutic agent for bone metastasis. We examined the effects of methylumbelliferone, an inhibitor of hyaluronan synthesis and/or ZA on the tumorigenicity of one murine lung carcinoma and two human (A549, SK-MES-1) lung cancer cell lines in vitro. The interaction between methylumbelliferone and zoledronic acid was analyzed using Calcucyn software. With a murine bone metastasis model of lung cancer in vivo, we investigated the inhibitory effects and interaction of the two drugs on the progression of metastatic bone lesions. Methylumbelliferone or zoledronic acid treatment individually suppressed proliferation, migration and invasion of 3 cell lines, and combination treatment showed synergistic effects. Although methylumbelliferone as a single agent did not enhance apoptotic activity, it showed additive effects on apoptotic activity to those of zoledronic acid. Co-localization of CD44 and ezrin, which might be a pathway of hyaluronan signaling, was abrogated by methylumbelliferone treatment. Combination therapy showed additive inhibitory effects on metastatic bone lesions in vivo, which paralleled the inhibition of hyaluronan accumulation by methylumbelliferone, and inhibition of osteoclastogenesis. Although the detailed mechanisms underlying the synergistic or additive inhibitory effects of these two drugs should be further analyzed, inhibition of hyaluronan synthesis by methylumbelliferone is a promising novel therapeutic candidate for bone metastasis of lung cancer in addition to zoledronic acid.Clinical and Experimental Metastasis 01/2013; · 3.46 Impact Factor
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ABSTRACT: Chronic intense UV radiation is the main cause of epidermal tumors. Because hyaluronan (HA), a large extracellular polysaccharide, is known to promote malignant growth, hyaluronan expression was studied in a model in which long-term UV radiation (UVR) induces epidermal tumors. Mouse back skin was exposed three times a week for 10.5 months to UVR corresponding to one minimal erythema dose, processed for histology, and stained for hyaluronan and the hyaluronan receptor CD44. This exposure protocol caused epidermal hyperplasia in most of the animals; tumors, mainly squamous cell carcinomas (SCCs), were found in ~20% of the animals. Specimens exposed to UVR showed increased hyaluronan and CD44 staining throughout the epidermal tissue. In hyperplastic areas, hyaluronan and CD44 stainings correlated positively with the degree of hyperplasia. Well-differentiated SCCs showed increased hyaluronan and CD44 staining intensities, whereas poorly differentiated tumors and dysplastic epidermis showed areas where HA and CD44 were locally reduced. The findings indicate that HA and CD44 increase in epidermal keratinocytes in the premalignant hyperplasia induced by UV irradiation and stay elevated in dysplasia and SCC, suggesting that the accumulation of hyaluronan and CD44 is an early marker for malignant transformation and may be a prerequisite for tumor formation.Journal of Histochemistry and Cytochemistry 08/2011; 59(10):908-17. · 2.26 Impact Factor