Hyaluronidases and hyaluronan synthases expression is inversely correlated with malignancy in lung/bronchial pre-neoplastic and neoplastic lesions, affecting prognosis

Abstract

We collected a series of 136 lung/bronchial and 56 matched lung parenchyma tissue samples from patients who underwent lung/bronchial biopsies and presented invasive carcinoma after lung surgery. The lung/bronchial samples included basal cell hyperplasia, squamous metaplasia, moderate dysplasia, adenomatous hyperplasia, severe dysplasia, squamous cell carcinoma and adenocarcinoma. Matched lung parenchyma tissue samples included 25 squamous cell carcinomas and 31 adenocarcinomas. Immunohistochemistry was performed to analyze for the distribution of hyaluronidase (Hyal)-1 and −3, and hyaluronan synthases (HAS)-1, −2, and −3. Hyal-1 showed significantly higher expression in basal cell hyperplasia than in moderate dysplasia (P=0.01), atypical adenomatous hyperplasia (P=0.0001), or severe dysplasia (P=0.03). Lower expression of Hyal-3 was found in atypical adenomatous hyperplasia than in basal cell hyperplasia (P=0.01) or moderate dysplasia (P=0.02). HAS-2 was significantly higher in severe dysplasia (P=0.002) and in squamous metaplasia (P=0.04) compared with basal cell hyperplasia. HAS-3 was significantly expressed in basal cell hyperplasia compared with atypical adenomatous hyperplasia (P=0.05) and severe dysplasia (P=0.02). Lower expression of HAS-3 was found in severe dysplasia compared with squamous metaplasia (P=0.01) and moderate dysplasia (P=0.01). Epithelial Hyal-1 and −3 and HAS-1, −2, and −3 expressions were significantly higher in pre-neoplastic lesions than in neoplastic lesions. Comparative Cox multivariate analysis controlled by N stage and histologic tumor type showed that patients with high HAS-3 expression in pre-neoplastic cells obtained by lung/bronchial biopsy presented a significantly higher risk of death (HR=1.19; P=0.04). We concluded that localization of Hyal and HAS in lung/bronchial pre-neoplastic and neoplastic lesions was inversely related to malignancy, which implied that visualizing these factors could be a useful diagnostic procedure for suspected lung cancer. Finalizing this conclusion will require a wider study in a randomized and prospective trial.

Hijacking the Hexosamine Biosynthetic Pathway to Promote EMT-Mediated Neoplastic Phenotypes

“…Low levels of UDP–GlcNAc are associated with an inhibition of HA synthesis, whereas elevated levels of UDP–GlcNAc are associated with HA synthesis and melanoma progression ( 126 ). Consistent with these data, several studies have demonstrated patients with higher extracellular HA or HAS expression have a worse prognosis and survival with more aggressive and metastatic cancers including breast ( 127 – 129 ), prostate ( 130 , 131 ), lung ( 132 , 133 ), pancreatic ( 134 ), colorectal ( 135 ), and ovarian ( 136 ) cancers. With respect to EMT, high levels of HA are sufficient to induce the EMT in kidney and mammary epithelial cells ( 137 ).…”

Hyaluronic Acid: Redefining Its Role

“…In fact, it has been shown that in many types of solid tumors, increased synthesis of HA by cancer cells or by tumor stromal cells is correlated with tumor growth and metastasis [ 9 , 142 ]. Recent studies have confirmed that the over-expression of HAS2 promotes tumor progression in breast, ovarian, bladder, colorectal, pancreatic and lung carcinoma and resistance to chemotherapy [ 143 , 144 , 145 , 146 , 147 , 148 ]. On the other hand, it was proved that inhibiting HA synthesis inhibits also metastasis of carcinoma cells in some types of tumors [ 144 , 149 ].…”

The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity

“…Artificial overexpression of HAS enzymes causes increased tumor growth in mouse xenograft models of prostate, breast and colon carcinomas while its knockdown reverses this phenotype ( Kultti et al, 2006 ; Koistinen et al, 2015 ). Further, HA is cleaved by hyaluronidases which have been suggested to act as tumor suppressors; whereby increased expression inhibits tumor growth in colon and breast xenografts ( Bertrand et al, 2005 ; Junker et al, 2003 ; Sá et al, 2015 ). Increased HA levels are correlated with formation of less dense matrices to facilitate invasion and promote angiogenesis.…”