Role of the extracellular matrix in variations of invasive pathways in lung cancers

Abstract

Among the most common features of highly invasive tumors, such as lung adenocarcinomas (AD) and squamous cell carcinomas (SqCC), is the massive degradation of the extracellular matrix. The remarkable qualitative and quantitative modifications of hyaluronidases (HAases), hyaluronan synthases (HAS), E-cadherin adhesion molecules, and the transforming growth factor β (TGF-β) may favor invasion, cellular motility, and proliferation. We examined HAase proteins (Hyal), HAS, E-cadherin, and TGF-β profiles in lung AD subtypes and SqCC obtained from smokers and non-smokers. Fifty-six patients, median age 64 years, who underwent lobectomy for AD (N = 31) and SqCC (N = 25) were included in the study. HAS-1, -2 and -3, and Hyal-1 and -3 were significantly more expressed by tumor cells than normal and stroma cells (P < 0.01). When stratified according to histologic types, HAS-3 and Hyal-1 immunoreactivity was significantly increased in tumor cells of AD (P = 0.01) and stroma of SqCC (P = 0.002), respectively. Tobacco history in patients with AD was significantly associated with increased HAS-3 immunoreactivity in tumor cells (P < 0.01). Stroma cells of SqCC from non-smokers presented a significant association with HAS-3 (P < 0.01). Hyal, HAS, E-cadherin, and TGF-β modulate a different tumor-induced invasive pathway in lung AD subgroups and SqCC. HAases in resected AD and SqCC were strongly related to the prognosis. Therefore, our findings suggest that strategies aimed at preventing high HAS-3 and Hyal-1 synthesis, or local responses to low TGF-β and E-cadherin, may have a greater impact in lung cancer prognosis.

Tissue hyaluronan expression, as reflected in the sputum of lung cancer patients, is an indicator of malignancy

“…Because cell-extracellular matrix interactions participate in several steps required for tumor cell invasion and formation of metastases, a group of glycosaminoglycans has been targeted as a potentially useful tumor marker (4,5). Among these glycosaminoglycans, hyaluronan (HA) has shown promise.…”

Roles and targeting of the HAS/hyaluronan/CD44 molecular system in cancer

“…Histologically, adenocarcinomas (AD) and squamous cell carcinomas (SCC) are the two most common carcinoma subtypes, accounting for ~90% of all lung cancer in most countries. Similarly to prostate cancer, HAS3 and HYAL1 were significantly increased also in lung cancer, specifically in AD and SCC [52]. Additionally, elevated HAS3 expression was correlated to patients with smoking history, whereas HYAL1 was strongly related to the lung prognosis [52].…”

“…Similarly to prostate cancer, HAS3 and HYAL1 were significantly increased also in lung cancer, specifically in AD and SCC [52]. Additionally, elevated HAS3 expression was correlated to patients with smoking history, whereas HYAL1 was strongly related to the lung prognosis [52]. The level of HA exceeding 75 µg HA-derived uronic acid (230 µg HA) per mL in effusion is strongly indicating a mesothelioma, whereas benign effusions often contain less than 10 µg HA-derived uronic acid (30 µg HA) per mL.…”

HABP2 is a Novel Regulator of Hyaluronan-Mediated Human Lung Cancer Progression

“…Further, accumulation of LMW-HA is correlated with cancer invasion and metastasis ( 63 ). In addition, the enzymatic proteins to produce HMW-HA and LMW-HA are upregulated in lung cancer including hyaluronan synthase 3 and hyaluronidase-1 ( 64 ). Although other HA-binding proteins are upregulated in lung cancer including CD44, RHAMM, and LYVE-1 ( 65 – 69 ); to the best of our knowledge, this is the first report of a functional role of HABP2 in HA-mediated lung cancer progression.…”