**1. Introduction**

Fucans are a family of polymeric molecules composed by a simple and long structure based on fucose and sulphate. Fucoidans are a subgroup within the fucan family, consisting of polysaccharides that are composed of sulphated l-fucose (6-deoxy-l-galactose) produced mainly by brown algae and, to a lesser extent, by marine invertebrates [1].

Due to the structural similarity between fucoidans and certain sulphated polysaccharides from animal cells, there has been increasing interest to study the biological properties of these algae polysaccharides within animal cells. An example for this are proteoglycans, which are found on the surface of animal cells and the extracellular matrix (ECM) and participate in structural and support functions. They have been shown to regulate a series of intercellular signaling pathways and interactions with cytokines and growth factors [2]. The structure of proteoglycans is similar to fucoidans, being composed of a protein (central chain) with glycosaminoglycans (GAGs) ramifications (e.g., chondroitin, dermatan, keratan, heparan sulphates, and heparin). This finding has sparked a renewed interest for studying the numerous potential biological properties including the anticoagulant [3], antioxidant [4], antiviral, immunomodulatory, anticomplement, and antitumor [5] characteristics of fucoidans isolated from di fferent brown algae species.

The chemical variety of fucans in algae and invertebrate, their abundant bioavailability in nature as a renewable natural resource available from our coasts [5] and their potential use for biomedicine, make these polysaccharides an interesting material to study. This review will reveal not only structural

characteristics but also the cellular/molecular aspects of fucoidans and their potential applications for cancer due to their properties to reduce metastasis and drug resistance in the different in vivo and in vitro cancer models.

## **2. General Structure of Fucoidans**

Fucoidans from algae have been extensively studied since 1913 when Prof. Kylin discovered and described fucoidans [6]. Then, in 1957 these molecules were also shown to have anticoagulant functions and subsequently their anticancer activities were demonstrated (1970) [7].

As described above, fucoidans are polysaccharide composed by sulphated l-fucose (6-deoxy-l-galactose) [8]. Although many fucoidans consist of fucose and sulphate groups as is typical for fucans in general, fucoidans—in contrast to other fucans—consist of up to 10% of other monosaccharides (mannose, galactose, glucose, xylose, etc.), uronic acids, or branches of one or more monosaccharides [5]. In addition, there are fucoidans with different monosaccharide residues alternating with α (1→3) and α (1→4) bonds. Therefore, fucoidans constitute a highly variable and versatile subgroup of fucans [9] (Figure 1).

**Figure 1.** Comparison between fucoidan and glycosaminoglycan structures. (**A**) Structure of fucoidan from the brown alga *Fucus vesiculosus* and (**B**) structure of chondroitin sulphate. It is important to remark the similarity in the sugar skeleton and the presence of sulphate groups (red) in both structures. "R" represents a fucose subunit without sulphate.

For instance, fucoidans from *Fucus vesiculosus* are composed of l-fucopyranosil residues linked through α (1→2) bonds with 4-position sulphate groups [10]. In addition, next generation techniques have shown that the scaffold is also composed by fucose residues linked through α (1→3) bonds with 4-position sulphate groups from some of the fucose residues disposed every two or three units of the main chain [11]. In contrast, other algae species contain the typical fucan complexes. *Sargassum stenophyllum* contains two types of fucans: (1) fucans containing predominantly <sup>α</sup>-<sup>l</sup>-fucose with high percentage of glucuronic acid and low amounts of sulphate located in different positions in the sugar [12] (2) fucans containing high amounts of sulphate but lower content of uronic acids distributed along the fucose chains or the only other sugar, galactose [12].

A wide range of l-fucose polymers has been found by fractionating the extracts from different algae species within the brown seaweed genus [3,13–20]. These fucoidans range from fractions of typical sulphated fucoidans to heteropolymer fractions of low-sulphate fucose and others containing glucosamine. The fucoidan structures vary from species to species, by season, location and maturity [21]. This structural variations are important for industrial applications to identify the optimum harvesting times and to ensure a consistent product composition. For instance, Fletcher et al., 2017 found that the highest quantity of fucoidans can be extracted from three algae *F. serratus*, *F. vesiculosus*, and *Ascophyllum nodosum* in autumn, whereas in spring the amount that can be obtained is at a minimum [21].

In addition to brown seaweed species, also marine invertebrates contain this type of sulphated polysaccharides. The viscous liquid containing sea urchin eggs, such as that of the *Strongylocentrotus franciscanus* species, contains a compound composed by sulphate acids residues only in position 2 bonds through α (1→3) bonds [22]. Other fucoidans have been found in the skin of the sea cucumber species *Stichopus japonicas* [23] and the recently commercially important *Holothuria tubulosa* [24].

The grea<sup>t</sup> diversity of fucoidans and their capability to be chemically modified make them molecules with grea<sup>t</sup> potential to be used as adjuvant agents in the treatment of cancer.
