Crude Fucoidan Extracts Impair Angiogenesis in Models Relevant for Bone Regeneration and Osteosarcoma via Reduction of VEGF and SDF-1

Abstract

The marine origin polysaccharide fucoidan combines multiple biological activities. As demonstrated by various studies in vitro and in vivo, fucoidans show anti-viral, anti-tumor, anti-oxidant, anti-inflammatory and anti-coagulant properties, although the detailed molecular action remains to be elucidated. The aim of the present study is to assess the impact of crude fucoidan extracts, on the formation of vascular structures in co-culture models relevant for bone vascularization during bone repair and for vascularization processes in osteosarcoma. The co-cultures consisted of bone marrow derived mesenchymal stem cells, respectively the osteosarcoma cell line MG63, and human blood derived outgrowth endothelial cells (OEC). The concentration dependent effects on the metabolic activity on endothelial cells and osteoblast cells were first assessed using monocultures of OEC, MSC and MG63 suggesting a concentration of 100 µg/mL as a suitable concentration for further experiments. In co-cultures fucoidan significantly reduced angiogenesis in MSC/OEC but also in MG63/OEC co-cultures suggesting a potential application of fucoidan to lower the vascularization in bone tumors such as osteosarcoma. This was associated with a decrease in VEGF (vascular endothelial growth factor) and SDF-1 (stromal derived factor-1) on the protein level, both related to the control of angiogenesis and furthermore discussed as crucial factors in osteosarcoma progression and metastasis. In terms of bone formation, fucoidan slightly lowered on the calcification process in MSC monocultures and MSC/OEC co-cultures. In summary, these data suggest the suitability of lower fucoidan doses to limit angiogenesis for instance in osteosarcoma.

Fucoidan Inhibition of Osteosarcoma Cells is Species and Molecular Weight Dependent

“…Fucoidans from various different species of brown seaweed have been studied for anti-cancer applications. While most of the research revolves around more common forms of cancer, such as breast and colon cancer [6], use of fucoidan against osteosarcoma has recently been a keen area of interest [31][32][33], as even though it is a relatively less common cancer, the implications can be severe [34]. For the first time, here, we investigated the variable effects of crude fucoidan derived from two different species of brown algae, namely, F. vesiculosus (commercial source) and S. filipendula (derived from Colombian coast), and further evaluated the effect of different molecular weight fractions from 10-50 kDa (LMW), 50-100 kDa (MMW) and >100 kDa (HMW) fractions of fucoidan from S. filipendula on MG63 human osteosarcoma cells.…”

“…The results showed that overall, HeLa 229 and A2780 cells were more strongly inhibited than HepG2 and LLC-PK1 cells, and even though the maximal sulphate content was found in the >100 kDa fraction, the cytotoxic activity was maximal for the 5-30 kDa fraction.Anti-tumor or anti-cancer activities of different fucoidans havebeen widely investigated for breast cancer [7,[21][22][23][24], colon/colorectal cancer [3,[25][26][27][28], liver cancer [13,29], lymphoma [8] and lung cancer [11,30]. However, the effect of fucoidan on osteosarcoma has only recently been investigated [31][32][33].Osteosarcoma is the most common type of bone cancer occurring in the proximal humerus (usually around the knee), distal femur and proximal tibia of younger children (more than 5 years of age), teenagers (it is the third most common cancer in adolescence) and older adults [34]. Currently, neoadjuvant and adjuvant chemotherapies, before and after surgery, are used for treating osteosarcoma.…”

“…Anti-tumor or anti-cancer activities of different fucoidans havebeen widely investigated for breast cancer [7,[21][22][23][24], colon/colorectal cancer [3,[25][26][27][28], liver cancer [13,29], lymphoma [8] and lung cancer [11,30]. However, the effect of fucoidan on osteosarcoma has only recently been investigated [31][32][33].…”

Stromal-Cell-Derived Factor (SDF) 1-Alpha Overexpression Promotes Bone Regeneration by Osteogenesis and Angiogenesis in Osteonecrosis of the Femoral Head

“…Moreover, several studies suggested that SDF-1 is closely associated with angiogenesis, which is essential for osteogenesis [35]. Importantly, the downregulation of SDF-1 achieved by treatment with crude fucoidan extract lowered the vascularization in osteosarcoma [36]. In addition, melittin was established to decrease the endothelial progenitor cell-mediated angiogenesis via SDF-1α inhibition in osteosarcoma [37].…”

Fucoidan Inhibition of Osteosarcoma Cells is Species and Molecular Weight Dependent

“…Antitumor or anticancer activities of different fucoidans have widely been investigated for breast cancer [7,[21][22][23][24], colon/colorectal cancer [3,[25][26][27][28], liver cancer [13,29], lymphoma [8] and lung cancer [11,30]. However, the effect of fucoidan on osteosarcoma has only recently been investigated [31][32][33].…”