The properties and behavior of tumor cells are closely regulated by their microenvironment. Accordingly, stromal cells and extracellular matrix components can have a pronounced effect on cancer initiation, growth, and progression. The linear glycosaminoglycan hyaluronan (HA) is a major component of the extracellular matrix. Altered synthesis and degradation of HA in the tumor context has been implicated in many aspects of tumor biology. In particular, the accumulation of small HA oligosaccharides (sHA) in the tumor interstitial space may play a decisive role, due to the ability of sHA to activate a number of biological processes that are not modulated by high molecular weight (HMW)-HA. In this article, we review the normal physiological role and metabolism of HA and then survey the evidence implicating HA in tumor growth and progression, focusing in particular on the potential contribution of sHA to these processes.

During tissue injury, inflammation, and tumor growth, enhanced production and degradation of the extracellular matrix glycosaminoglycan hyaluronan (HA) can lead to the accumulation of small HA (sHA) oligosaccharides. We have previously reported that accumulation of sHA in colorectal tumors correlates with lymphatic invasion and lymph node metastasis, and therefore, investigated here are the effects of sHA on the lymphatic endothelium. Using cultured primary lymphatic endothelial cells (LECs) and ex vivo and in vivo lymphangiogenesis assays, we found that in contrast to high-molecular-weight HA (HMW-HA), sHA of 4-25 disaccharides in length can promote the proliferation of LECs and lymphangiogenesis in a manner that is dependent on their size and concentration. At pathophysiologically relevant concentrations found in tumor interstitial fluid, sHA is pro-proliferative, acts synergistically with VEGF-C and FGF-2, and stimulates the outgrowth of lymphatic capillaries in ex vivo lymphangiogenesis assays. In vivo, intradermally injected sHA acts together with VEGF-C to increase lymphatic vessel density. Higher concentrations of sHA were found to induce expression of the anti-lymphangiogenic cytokine TGFβ in LECs, which serves to counter-regulate sHA-induced LEC proliferation and lymphangiogenesis. Using appropriate knockout mice and blocking antibodies, we found that the effects of sHA are mediated by the sialylated form of the lymphatic HA receptor LYVE-1, but not by CD44 or TLR-4. These data are consistent with the notion that accumulation of sHA in tumors may contribute to tumor-induced lymphangiogenesis, leading to increased dissemination to regional lymph nodes. KEY MESSAGES : sHA promotes lymphangiogenesis primarily through increased LEC proliferation sHA induces proliferation in a narrow concentration window due to upregulated TGFβ Smaller HA oligosaccharides more potently induce proliferation than larger ones VEGF-C and FGF-2-induced LEC proliferation and lymphangiogenesis is augmented by sHA Sialylated LYVE-1, but not CD44 or TLR-4, mediate the effects of sHA on LEC.

Purpose: Photon-based radiation therapy does currently not play a major role as local ablative treatment for hepatocellular carcinoma (HCC). Carbon ions offer distinct physical and biological advantages. Due to their inverted dose profile and the high local dose deposition within the Bragg peak, precise dose application and sparing of normal tissue is possible. Furthermore, carbon ions have an increased relative biological effectiveness (RBE) compared to photons. Methods and materials:A total of six patients with one or more HCC-lesions were treated with carbon ions delivered by the raster-scanning technique according to our clinical trial protocol. Diagnosis of HCC was confirmed by histology or two different imaging modalities (CT and MRI) according to the AASLD-guidelines. Applied fractionation scheme was 4 × 10 Gy(RBE). Correct dose application was controlled by in-vivo PET measurement of β + −activity in the irradiated tissue shortly after treatment.

In patients with low-risk breast cancer, intraoperative radiotherapy (IORT) during breast-conserving surgery is a novel and convenient treatment option for delivering a single high dose of irradiation directly to the tumour bed. However, edema and fibrosis can develop after surgery and radiotherapy, which can subsequently impair quality of life. TGF- β is a strong inducer of the extracellular matrix component hyaluronan (HA). TGF-β expression and HA metabolism can be modulated by irradiation experimentally, and are involved in edema and fibrosis. We therefore hypothesized that IORT may regulate these factors.Wound fluid (WF) draining from breast lumpectomy sites was collected and levels of TGF-β1 and HA were determined by ELISA. Proliferation and marker expression was analyzed in primary lymphatic endothelial cells (LECs) treated with recombinant TGF-β or WF. Our results show that IORT does not change TGF-β1 or HA levels in wound fluid draining from breast lumpectomy sites, and does not lead to accumulation of sHA oligosaccharides. Nevertheless, concentrations of TGF-β1 were high in WF from patients regardless of IORT, at concentrations well above those associated with fibrosis and the suppression of LEC identity. Consistently, we found that TGF-β in WF is active and inhibits LEC proliferation. Furthermore, all three TGF-β isoforms inhibited LEC proliferation and suppressed LEC marker expression at pathophysiologically relevant concentrations.Given that TGF-β contributes to edema and plays a role in the regulation of LEC identity, we suggest that inhibition of TGF-β directly after surgery might prevent the development of side effects such as edema and fibrosis.