Accumulation of small hyaluronan oligosaccharides in tumour interstitial fluid correlates with lymphatic invasion and lymph node metastasis

Abstract

Background:Association studies have implicated the glycosaminoglycan hyaluronan (hyaluronic acid, HA) and its degrading enzymes the hyaluronidases in tumour progression and metastasis. Oligosaccharides of degraded HA have been ascribed a number of biological functions that are not exerted by high-molecular-weight HA (HMW-HA). However, whether these small HA oligosaccharides (sHA) have a role in tumour progression currently remains uncertain due to an inability to analyse their concentration in tumours.Methods:We report a novel method to determine the concentration of sHA ranging from 6 to 25 disaccharides in tumour interstitial fluid (TIF). Levels of sHA were measured in TIF from experimental rat tumours and human colorectal tumours.Results:While the majority of HA in TIF is HMW-HA, concentrations of sHA up to 6 μg ml−1 were detected in a subset of tumours, but not in interstitial fluid from healthy tissues. In a cohort of 72 colorectal cancer patients we found that increased sHA concentrations in TIF are associated with lymphatic vessel invasion by tumour cells and the formation of lymph node metastasis.Conclusions:These data document for the first time the pathophysiological concentration of sHA in tumours, and provide evidence of a role for sHA in tumour progression.

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion

“…1), a finding consistent with the notion that LMW-HA is associated with lymphatic vessel invasion by tumor cells. 10,11 We also found increases in tumor-draining lymphatic vessel diameter in LMW-HA-treated mice. This result is consistent with that of a recent study demonstrating that changes in the adhesive properties of the lymphatic endothelium near tumors are fundamental steps in tumor metastasis through the lymph vessel lumen.…”

“…9 More importantly, one study investigated the levels of hyaluronan fragments ranging from 6-25 disaccharides in the interstitial fluid of colorectal tumors, and found that elevated LMW-HA levels were associated with lymphatic vessel invasion by tumor cells and LN metastasis. 10 Similarly, our previous work showed that serum levels of LMW-HA, but not total HA, clearly correlated with LN metastasis in breast cancer. 11 Besides of these findings, LMW-HA has also been reported to induce lymphangiogenesis, 12 which is similar to the angiogenesis promoted by LMW-HA or hyaluronan fragments.…”

Hyaluronan stimulates pancreatic cancer cell motility

“…Elevated serum levels of LMW-HA (smaller than 50kDa), but not total HA, correlated with metastasis in patients with breast cancer and decreasing the LMW-HA levels inhibited the migration and invasion of breast cancer cells [11]. Furthermore, in human colorectal cancer tissues, accumulation of LMW-HA (ranging from 6 to 25 disaccharides) in tumor interstitial fluid correlated with lymphatic invasion and lymph node metastasis [12]. These and our present findings suggest that LMW-HA, rather than HMW-HA, contributes to tumor progression by increasing cancer cell motility.…”

“…For example, HA has been shown to promote tumor progression by enhancing cell proliferation, migration, invasion, metastasis, angiogenesis, and resistance to chemotherapeutic agents [9,10]. Interestingly, lowmolecular-weight HA (LMW-HA), rather than highmolecular-weight HA (HMW-HA), has been shown to be specifically accumulated in cancer tissues and involved in tumor progression [11][12][13].…”

Inhibition of Systemic Hyaluronan Synthesis Exacerbates Murine Hepatic Carcinogenesis

“…During tissue injury, HA is actively produced for tissue repair with regulation of epithelial cell and fibroblast behavior (8,9). In regard to cancer, many previous studies have demonstrated that stromal HA may create a permissive extracellular microenvironment for tumor progression and metastasis through cancer cell proliferation, migration, and invasion (10)(11)(12)(13)(14)(15)(16)). An increase in HA deposits has been correlated with poor clinical prognosis in pancreatic, colorectal, ovarian, and breast cancer (17).…”