The roles of HA, HAS, Hyal, and HA receptors in cancer biology are complex and mediated by HA receptors expressed in cancer cells [
133]. Hence, it was suggested that HA was proposed as a drug carrier or to design nanoparticles or lposomes for its biocompatibility, biodegradability and on the basis of CD44 ability to internalize HA [
134,
135,
136,
137]. Carrier drug systems are considered promising cancer therapeutics for the delivery of cytotoxic drugs and many in vivo studies have proven the safety and efficacy of targeted therapy with HA-anti cancer drugs [
138,
139]. Moreover, HA and its derivatives are promising materials for liposomes functionalization which can delay the release of drugs and enhance local bioavailability. Additionally, HA has recently been proposed to detect CD44 in the diagnosis of specific tumors and recently targeted molecular imaging with HA as specific magnetic resonance contrast agents have been suggested for the diagnosis and treatment of CD44-overexpressing cancer [
140,
141]. Up to now, cancer therapy with HA-anti-tumoural conjugates appears to be a potentially successful approach in the near future if technical difficulties are resolved. However, a better understanding of the role of HAS, Hyal in cancer biology may lead to their successful clinical usage for cancer treatment. In fact, it has been shown that in many types of solid tumors, increased synthesis of HA by cancer cells or by tumor stromal cells is correlated with tumor growth and metastasis [
9,
142]. Recent studies have confirmed that the over-expression of HAS2 promotes tumor progression in breast, ovarian, bladder, colorectal, pancreatic and lung carcinoma and resistance to chemotherapy [
143,
144,
145,
146,
147,
148]. On the other hand, it was proved that inhibiting HA synthesis inhibits also metastasis of carcinoma cells in some types of tumors [
144,
149]. However, other studies reported that HAS3 that was associated with tumor progression, downregulate in early tumor development. For these reasons, it was proposed as a prospective prognostic biomarker and a novel therapeutic target in urothelial carcinoma of the upper urinary tract and urinary bladder [
150]. In other types of cancers, progression is not influenced by the HA accumulation but rather by its fragmentation [
151]. The degradation of HA in a broad range of its molecular sizes is stimulated by Hyals and tissue ROS that are abundant in tumor microenvironments. In particular, the over-expression of Hyal-1 and Hyal-2 was reported during cancer metastasis in many in vitro and in vivo studies [
152,
153] and recently it was suggested that HA fragments promote cancer progression via Hippo-Yap signaling [
154]. However, the role of Hayl-3 in cancer progression is controversial since some studies have demonstrated its prevention of tumor growth [
142], whereas others reported an increased amount of the molecule in some solid tumors [
155]. Based on emerging evidence, it was also suggested that specific size ranges of low MW HA exert differential effects on tumor cell survival and growth as recently reviewed by Tavianatou AG et al. [
17]. MW HA binds to ECM molecules and cell receptors activating signaling networks for angiogenesis, cell proliferation and extravasation in the microenvironment surrounding metastatic lesions [
156]. Small HA fragments are associated with more aggressive solid tumors and recent studies have proven that antibodies or small HA oligomers that inhibit their binding to HA cell receptors are effective in disrupting invasion of tumor cells [
157,
158,
159]. In fact, as previously reported, HA of various MW interact with its two major cell surface receptors, CD44 and RHAMM that act independently or as co-receptors to trigger downstream signaling which enhances tumor progression [
160]. However, adaptations in the HA receptor genes CD44 and RHAMM were found in resistant tumors, in breast and colon carcinomas [
31]. The correlation between CD44 and tumourigenicity is not absolute since discordant results have been reported [
161,
162]. In particular, several isoforms of CD44 (CD44v) are up-regulated mostly by cancer cells and necessary for cell cancer invasion. In particular, several isoforms of CD44 (CD44v) are up-regulated mostly by cancer cells and necessary for cell cancer invasion [
163]. Thus these receptors have been identified as targets in the treatment of specific cancers directly associated with CD44 since the inhibition of the interaction HA-receptors might result in complete abrogation of tumor progression [
164]. Only a few of the described therapeutics have been tested clinically and no HA-based drug delivery systems for human anticancer therapies are actually in clinical use. However, they clearly demonstrated the potential for future use as cancer therapy.