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Hyaluronic Acid Increases Cancer

by Dr. Loren Pickart
BA, Chemistry and Mathematics, University of Minnesota
PhD, Biochemistry, University of California, San Francisco

Discoverer of GHK-Cu and many of the effects of copper peptides

We have had many questions about Hyaluronic Acid. You should not use cosmetic products containing hyaluronic acid especially if you are over the age of 30. Higher hyaluronic acid levels promote cancer growth and metastasis. While such cancers may not develop for many years, it is good to remember that the effects of cigarette smoking only became evident with time.

If you put in "hyaluronic acid cancer" in PubMed, over 4,015 articles are referenced.

The heavily-advertised beauty industry has been, and still is, filled with skin damaging treatments that are repeated about every four months for revenue enhancement. For example, silicone injections were widely used for years and now the US FDA says they are extremely dangerous. Bovine collagen was used as a filler and was said to be non-allergic. However in time, this collagen often produced hard bumps under the skin. We hear many complaints about repeated laser treatments that often result in a chronically inflamed skin. And the list goes on and on. Those performing such treatments seem to have little understanding of the human body's regenerative and protective systems.

The following reasons are why Skin Biology refuses to use hyaluronic acid:


For Your Long Term Health, Avoid the Cosmetic Hyaluronic Acid Hustlers

Hyaluronic acid (scientific name - hyaluronan) used in skin products is produced by various strains of pathogenic bacteria. In recent years its promotion for skin products is extensive and has been termed the HYPE TRAIN. It has been said to be super safe and not even enter your skin. However, actual science paints a very different picture of hyaluronic acid and your skin.

A British study found that the average woman using cosmetics retains 2.2 KG (4.85 pounds) of cosmetic ingredients in her body each year. So using a cancer accelerator for many years is dangerous.

Absorption of hyaluronan applied to the surface of intact skin.
Brown TJ1, Alcorn D, Fraser JR J Invest Dermatol. 1999 Nov;113(5):740-6 Hyaluronan has recently been introduced as a vehicle for topical application of drugs to the skin. We sought to determine whether hyaluronan acts solely as a hydrophilic reservoir on the surface of intact skin or might partly penetrate it. Drug-free hyaluronan gels were applied to the intact skin of hairless mice and human forearm in situ, with and without [3H] hyaluronan. [3H]hyaluronan was shown by autoradiography to disseminate through all layers of intact skin in mouse and human, reaching the dermis within 30 min of application in mice. Cellular uptake of [3H]hyaluronan was observed in the deeper layers of epidermis, dermis, and in lymphatic endothelium. Absorption through skin was confirmed in mice by chromatographic analysis of blood, urine, and extracts from skin and liver, which identified 3H as intact hyaluronan and its metabolites, free acetate and water. Hyaluronan absorption was similarly demonstrated without polyethylene glycol, which is usually included in the topical formulation. [3H]hyaluronan absorption was not restricted to its smaller polymers as demonstrated by the recovery of polymers of (360-400 kDa) from both blood and skin. This finding suggests that its passage through epidermis does not rely on passive diffusion but may be facilitated by active transport. This study establishes that hyaluronan is absorbed from the surface of the skin and passes rapidly through epidermis, which may allow associated drugs to be carried in relatively high concentration at least as far as the deeper layers of the dermis.



We are slowly building scientific references on this topic and will expand the references.


1. Targeting Hyaluronidase for Cancer Therapy: Antitumor Activity of Sulfated Hyaluronic Acid in Prostate Cancer Cells.
Anaid Benitez, Travis J. Yates, Luis E. Lopez, Wolfgang H. Cerwinka, Ashraf Bakkar and Vinata

The tumor cell–derived hyaluronidase (HAase) HYAL-1 degrades hyaluronic acid (HA) into proangiogenic fragments that support tumor progression. Although HYAL-1 is a critical determinant of tumor progression and a marker for cancer diagnosis and metastasis prediction, it has not been evaluated as a target for cancer therapy. Similarly, sulfated hyaluronic acid (sHA) has not been evaluated for biological activity, although it is an HAase inhibitor. In this study, we show that sHA is a potent inhibitor of prostate cancer. sHA blocked the proliferation, motility, and invasion of LNCaP, LNCaP-AI, DU145, and LAPC-4 prostate cancer cells, and induced caspase-8–dependent apoptosis associated with downregulation of Bcl-2 and phospho-Bad. sHA inhibited Akt signaling including androgen receptor (AR) phosphorylation, AR activity, nuclear factor κB (NFκB) activation, and VEGF expression.

These effects were traced to a blockade in complex formation between phosphoinositide 3-kinase (PI3K) and HA receptors and to a transcriptional downregulation of HA receptors, CD44, and RHAMM, along with PI3K inhibition. Angiogenic HA fragments or overexpression of myristoylated Akt or HA receptors blunted these effects of sHA, implicating a feedback loop between HA receptors and PI3K/Akt signaling in the mechanism of action.

In an animal model, sHA strongly inhibited LNCaP-AI prostate tumor growth without causing weight loss or apparent serum-organ toxicity. Inhibition of tumor growth was accompanied by a significant decrease in tumor angiogenesis and an increase in apoptosis index. Taken together, our findings offer mechanistic insights into the tumor-associated HA–HAase system and a preclinical proof-of-concept of the safety and efficacy of sHA to control prostate cancer growth and progression. Cancer Res; 71(12); 4085–95. ©2011 AACR.


2. More Than a Gel – Hyaluronic Acid, A Central Component In The Microenvironment Of Pancreatic Cancer.
Authors: Thomas Seufferlein, Michel Ducreux, Manuel Hidalgo, Gerald Prager, Eric Van Cutsem, European Oncology & Haematology. 2018;14(1):40–44

Hyaluronic acid or hyaluronan (HA) is a major stromal component and its accumulation has been shown to play a central role in promoting tumourigenesis and progression of disease. Thus, overexpression of HA in tumours is associated with poor prognosis. Therapeutic targeting of HA is therefore an attractive strategy, particularly in pancreatic ductal adenocarcinoma (PDA), which is associated with an extremely poor prognosis and less sensitivity towards chemotherapy. PDA is characterized by a high stromal content. The accumulation of dense, fibrotic extracellular matrix components within the stroma, termed desmoplasia, results in increased tumour interstitial fluid pressure and vascular compression that impair the delivery and efficacy of therapeutic agents. While some elements of the stroma may be protective for the patient and prevent a more aggressive phenotype of PDA, a pegylated recombinant human hyaluronidase (pegvorhyaluronidase alfa) has been found to inhibit tumour growth in preclinical studies.

In a clinical phase II randomized trial, the addition of pegvorhyaluronidase alfa to nab-paclitaxel and gemcitabine suggested significantly longer progression-free survival in patients with advanced PDA compared with nab-paclitaxel and gemcitabine alone. This benefit was even more pronounced in a subgroup of patients who expressed high levels of tumour HA.



3. Serum hyaluronan (hyaluronic acid) in breast cancer patients.
Bertrand Delpech, Bernard Chevallier, Nadine Reinhardt, Jean-Pierre Julien, Christian Duval, Catherine Maingonnat, Philippe Bastit, Bernard Asselain, International Journal of cancer, Volume46, Issue3, 15 September 1990, Pages 388-390

Eighty-three women with breast cancer (57 with systemic metastasis, 26 without) were investigated for serum hyaluronan (HA) and compared to 50 patients with benign diseases of the breast. Hyaluronan was significantly increased in sera of metastatic patients compared to sera of non-metastatic patients (p< 0.0001) and also in sera of non-metastatic patients when compared to control sera (p< 0.01). The difference was not related to the number of metastatic sites involved. Three months after starting cytotoxic chemotherapy in metastatic patients, lower HA concentrations were observed in patients responding to chemotherapy. The initial level of serum HA had no predictive value concerning response to chemotherapy.



4. Increased Synthesis of Hyaluronic Acid by Mouse Mammary Carcinoma Cell Variants with High Metastatic Potential.
Koji Kimata, Yoshio Honma, Minoru Okayama, Kayoko Oguri, Motoo Hozumi and Sakaru Suzuki, Cancer Research, March 1983, Volume 43, Issue 3

Variant subpopulations of FM3A mouse mammary carcinoma cells that have increased lung-colonizing potential were obtained previously by sequentially harvesting pulmonary metastases, culturing their cells in vitro, and reestablishing the metastases in vivo. In the present study, glycosaminoglycan production by the parental and variant cells was studied after metabolic labeling of cultures by [14C]glucosamine for 24 hr. Analysis of the products indicated that the rate of incorporation of the labeled precursor into hyaluronic acid in the high-metastatic variant cells was 27 to 54 times the rate in the low-metastatic cells and that the increase in hyaluronic acid synthesis was not associated with an increase in the rate of synthesis of other glycosaminoglycans. Both the cell layers and media of high-metastatic variants contained a much higher proportion of radioactivity in hyaluronic acid than did the corresponding fractions of low-metastatic cell lines.

The results provide a basis for further investigation of the potential role of hyaluronic acid in control of the behavior of epithelial tumor cells during metastasis.



5. Plasma hyaluronic acid level as a prognostic and monitoring marker of metastatic breast cancer.
Cike Peng, Anja Rudolph, Katarina Cuk, Ursula Eilber, Muhabbet Celik, Caroline Modugno, Andreas Trumpp, Jorg Heil, Frederik Marmé, Dharanija Madhavan, International Journal of Cancer Volume138, Issue10, May 15 2016, Pages 2499-250

Conventional tumor markers have limited value for prognostication and treatment monitoring in metastatic breast cancer (MBC) patients and novel circulating tumor markers therefore need to be explored. Hyaluronic acid (HA) is a major macropolysaccharide in the extracellular matrix and is reported to be associated with tumor progression. In our study, we investigated plasma HA level with respect to progression free survival (PFS) and overall survival (OS), as well as the treatment monitoring value in MBC patients. The prognostic value of plasma HA level was investigated in a discovery cohort of 212 MBC patients with 2.5-year follow-up and validated in an independent validation cohort of 334 patients with 5-year follow-up. The treatment monitoring value of plasma HA level was investigated in 61 MBC patients from discovery cohort who had been radiographically examined after first complete cycle of chemo therapy. We found a robust association between high plasma HA level and poor prognosis of MBC patients in both discovery (pPFS = 7.92 × 10−6 and pOS = 5.27 × 10−5) and validation studies (pPFS = 3.66 × 10−4 and pOS = 1.43 × 10−4). In the discovery cohort, the plasma HA level displayed independent prognostic value after adjusted for age and clinicopathological factors, with respect to PFS and OS. Further, the decrease of plasma HA level displayed good concordance with treatment response evaluated by radiographic examination (AUC = 0.79). Plasma HA level displays prognostic value, as well as treatment monitoring value for MBC patients.



6. Hyaluronic acid family in bladder cancer: potential prognostic biomarkers and therapeutic targets.
Daley S Morera, Martin S Hennig, Asif Talukder, Soum D Lokeshwar, Jiaojiao Wang, Michael Garcia-Roig, Nicolas Ortiz, Ravis J Yates, Luis E Lopez, Georgios Kallifatidis, Mario W Kramer, Andre R Jordan, Axel S Merseburger, Murugesan Manoharan, Mark S Soloway, Martha K Terris, Vinata B Lokeshwar. British Journal of Cancer 117, 1507–1517 (07 November 2017)

In clinical specimens and TCGA data sets, HA synthases and hyaluronidase-1 levels significantly predicted metastasis and poor survival. 4-Methylumbelliferone inhibited proliferation and motility/invasion and induced apoptosis in bladder cancer cells. Oral administration of 4MU both prevented and inhibited tumour growth, without dose-related toxicity. Effects of 4MU were mediated through the inhibition of CD44/RHAMM and phosphatidylinositol 3-kinase/AKT axis, and of epithelial–mesenchymal transition determinants. These were attenuated by HA, suggesting that 4MU targets oncogenic HA signaling. In tumour specimens and the TCGA data set, HA family expression correlated positively with β-catenin, Twist and Snail expression, but negatively with E-cadherin expression.



7. Hyaluronic Acid Synthase-1 Expression Regulates Bladder Cancer Growth, Invasion, and Angiogenesis through CD44.
Roozbeh Golshani, Luis Lopez, Veronica Estrella, Mario Kramer, Naoko Iida and Vinata B., Lokeshwar, Cancer Res. 2008 Jan 15;68(2):483-91.

Hyaluronic acid (HA) promotes tumor metastasis and is an accurate diagnostic marker for bladder cancer. HA is synthesized by HA synthases HAS1, HAS2, or HAS3. We have previously shown that HAS1 expression in tumor tissues is a predictor of bladder cancer recurrence and treatment failure. In this study, we stably transfected HT1376 bladder cancer cells with HAS1-sense (HAS1-S), HAS1-antisense (HAS1-AS), or vector cDNA constructs.

Whereas HAS1-S transfectants produced approximately 1.7-fold more HA than vector transfectants, HA production was reduced by approximately 70% in HAS1-AS transfectants. HAS1-AS transfectants grew 5-fold slower and were approximately 60% less invasive than vector and HAS1-S transfectants. HAS1-AS transfectants were blocked in G(2)-M phase of the cell cycle due to down-regulation of cyclin B1, cdc25c, and cyclin-dependent kinase 1 levels. These transfectants were also 5- to 10-fold more apoptotic due to the activation of the Fas-Fas ligand-mediated extrinsic pathway. HAS1-AS transfectants showed a approximately 4-fold decrease in ErbB2 phosphorylation and down-regulation of CD44 variant isoforms (CD44-v3, CD44-v6, and CD44-E) both at the protein and mRNA levels. However, no decrease in RHAMM levels was observed. The decrease in CD44-v mRNA levels was not due to increased mRNA degradation. Whereas CD44 small interfering RNA (siRNA) transfection decreased cell growth and induced apoptosis in HT1376 cells, HA addition modestly increased CD44 expression and cell growth in HAS1-AS transfectants, which could be blocked by CD44 siRNA. In xenograft studies, HAS1-AS tumors grew 3- to 5-fold slower and had approximately 4-fold lower microvessel density. These results show that HAS1 regulates bladder cancer growth and progression by modulating HA synthesis and HA receptor levels.



8. Tumor-associated Hyaluronic Acid: A New Sensitive and Specific Urine Marker for Bladder Cancer.
Vinata B. Lokeshwar, Can Öbek, Mark S.,Soloway and Norman L.Block, Cancer Research, February 1997, Volume 57, Issue 4

Hyaluronic acid (HA), a glycosaminoglycan, is known to promote tumor cell adhesion and migration, and its small fragments stimulate angiogenesis. We compared levels of HA in the urine of normal individuals and patients with bladder cancer or other genitourinary conditions, using a sensitive ELISA-like assay. Among the 144 specimens analyzed, the urinary HA levels of bladder cancer patients with G1 (255 ± 41.7 ng/mg), G2 (291.8 ± 68.3 ng/mg) and G3 (428.4 ± 67 ng/mg) tumors are 4–9-fold elevated as compared to those of normal individuals (44.7 ± 6.2 ng/mg) and patients with other genitourinary conditions (69.5 ± 6.8 ng/mg; P < 0.001). Urinary HA measurement by the ELISA-like assay shows a sensitivity of 91.9% and specificity of 92.8% to detect bladder cancer. Thus, urinary HA measurement is a simple, noninvasive yet highly sensitive and specific method for bladder cancer detection.

The increase in urinary HA concentration is a direct correlate of the elevated tumor-associated HA levels, because the HA levels are also elevated (3–5-fold) in bladder tumor tissues (P < 0.001). The profiles of urinary HA species of normal individuals and bladder cancer patients are different. Although only the intermediate-size HA species are found in the urine of normal and low-grade bladder tumor patients, the urine of high-grade bladder cancer patients contains both the high molecular mass and the small angiogenic HA fragments. These urinary HA fragments stimulate a mitogenic response (2.4-fold) in primary human microvessel endothelial cells, suggesting that the small HA fragments may regulate tumor angiogenesis by modulating endothelial cell functions.



9. Hyaluronic Acid Synthase-1 Expression Regulates Bladder Cancer Growth, Invasion, and Angiogenesis through CD44.
Roozbeh Golshani, Luis Lopez, Veronica Estrella, Mario Kramer, Naoko Iida and Vinata B. Lokeshwar, Cancer Research, January 2008, Volume 68, Issue 2.

Hyaluronic acid (HA) promotes tumor metastasis and is an accurate diagnostic marker for bladder cancer. HA is synthesized by HA synthases HAS1, HAS2, or HAS3. We have previously shown that HAS1 expression in tumor tissues is a predictor of bladder cancer recurrence and treatment failure. In this study, we stably transfected HT1376 bladder cancer cells with HAS1-sense (HAS1-S), HAS1-antisense (HAS1-AS), or vector cDNA constructs. Whereas HAS1-S transfectants produced ∼1.7-fold more HA than vector transfectants, HA production was reduced by ∼70% in HAS1-AS transfectants. HAS1-AS transfectants grew 5-fold slower and were ∼60% less invasive than vector and HAS1-S transfectants. HAS1-AS transfectants were blocked in G2-M phase of the cell cycle due to down-regulation of cyclin B1, cdc25c, and cyclin-dependent kinase 1 levels. These transfectants were also 5- to 10-fold more apoptotic due to the activation of the Fas-Fas ligand–mediated extrinsic pathway. HAS1-AS transfectants showed a ∼4-fold decrease in ErbB2 phosphorylation and down-regulation of CD44 variant isoforms (CD44-v3, CD44-v6, and CD44-E) both at the protein and mRNA levels. However, no decrease in RHAMM levels was observed. The decrease in CD44-v mRNA levels was not due to increased mRNA degradation. Whereas CD44 small interfering RNA (siRNA) transfection decreased cell growth and induced apoptosis in HT1376 cells, HA addition modestly increased CD44 expression and cell growth in HAS1-AS transfectants, which could be blocked by CD44 siRNA. In xenograft studies, HAS1-AS tumors grew 3- to 5-fold slower and had ∼4-fold lower microvessel density.

These results show that HAS1 regulates bladder cancer growth and progression by modulating HA synthesis and HA receptor levels. [Cancer Res 2008;68(2):483–91]



10. Hyaluronic Acid-stimulating Activity in Sera from the Bovine Fetus and from Breast Cancer Patients.
Margaret Decker, Ernest S. Chiu, Charles Dollbaum, Ali Moiin, Jackson Hall, Rex Spendlove, Michael T. Longaker and Robert Stern, Cancer Research, July 1989 Volume 49, Issue 13.

The sine qua non of malignancy is the ability of tumor cells to migrate and invade surrounding tissue. There are many substances that have been described that enhance cell motility and hyaluronic acid is prominent among these. Hyaluronic acid is a high molecular weight alternating disaccharide polymer found in abundance in extracellular matrices whenever rapid cell proliferation or tissue regeneration and repair occur. It creates a permissive environment for cell motility during embryogenesis, and high levels of hyaluronic acid also correlate with increased tumor cell invasion and aggressiveness.

Little is known about the regulation of hyaluronic acid production, either in normal tissue or in malignancy. In this study, we characterize a hyaluronic acid-stimulating activity in fetal calf serum and describe a similar activity in the sera of breast cancer patients. The stimulating activity was measured by placing aliquots of test substance on fibrosarcoma cells. These indicator cells, which synthesize copious quantities of hyaluronic acid, respond to stimulation in a time- and dose-dependent fashion. The fetal calf serum hyaluronic acid-stimulating activity is maximum early in gestation and then falls rapidly to essentially no activity at term. This activity was partially purified from 120-day fetal calf serum by concanavalin A-Sepharose affinity and ion exchange chromatography and is accounted for by a glycoprotein with a molecular weight of 150,000 on gel filtration under native conditions. The sera of breast cancer patients with measurable burden of disease also contained hyaluronic acid-stimulating activity, which was not present in normal serum donors or in breast cancer patients without evidence of disease.

The production of this stimulating activity may contribute to the development of the malignant phenotype by inducing hyaluronic acid-rich microenvironments that are permissive to tumor cell invasion and metastases.


11. Biochemical evaluation of hyaluronic acid in breast cancer.
Yahya RS, El-Bindary AA, El-Mezayen HA, Abdelmasseh HM, Eissa MA, Clin Lab. 2014;60(7):1115-21.

The latest experimental studie human cancer diseases have observed the bioactive role of hyaluronic acid (HA) during carcinogenesis. HA is a component of the extra-cellular matrix (ECM). It is closely correlated with tumor cell growth, proliferation, and metastasis. The present study aimed to evaluate the biochemical role of HA and its degrading enzymes and products in breast cancer (BC) patients under therapy treatments. An ELISA method was used to determine HA levels and standard spectrophotometric techniques were used to estimate the activities of HA degrading enzymes hyaluronidase (HAS), N-acetyl-beta-D-glucosminidase (NAG), and beta-glucuronidase (beta-Glu) and the concentration of both glucoseamine (G-Amine) and glucuronic acid (GA) as degrading products in blood sera of 50 BC patients before and after chemotherapy treatment and in blood sera of 40 healthy women as controls.

Elevated serum HA levels, increased HAS, NAG, and beta-Glu activities and high concentrations of G-Amine and GA were significantly found (p < 0.001) in patients before treatment compared to controls. After all BC patients had received the first chemotherapy course, HA and its previous degrading parameters were significantly decreased (p < 0.001) in post-treated patients compared to pre-treated patients. Hyaluronic acid and its degrading enzymes and products can be considered a biomarker for early detection of recurrent disease and also for monitoring the effective therapeutic follow up of BC patients.


12. Increase in hyaluronic acid degradation decreases the expression of estrogen receptor alpha.
Vincent Hanoux, Judith Eguida, Emmanuelle Fleurot, Jérôme Levallet, Pierre-JacquesBonnamy, Molecular and Cellular Endocrinology, Volume 476, 15 November 2018, Pages 185-197.

The loss of estrogen receptor α (ERα) expression in breast cancer constitutes a major hallmark of tumor progression to metastasis and is generally correlated to a strong increase in Hyaluronic Acid (HA) turnover. The aim of our study was to search for a putative link between these two major events of breast cancer progression in the estrogen receptor-positive (ER+) MCF7 breast cancer cell line.

The increase in HA turnover was performed by stable overexpression of the standard CD44 (CD44S) isoform and also by treatment with exogenous Hyaluronidase (Hyal) to allow an increase in HA catabolism. Stable overexpression of CD44S in MCF7 cells was correlated to a decrease in ESR1 gene expression, which did not lead to alteration of estrogen response. Moreover, our results showed that the exposure to exogenous Hyal stimulates the proliferation and strongly decreases the expression of ERα whatever the expression level of CD44 in the MCF7 cell line. The culture in the presence of Hyal led to the decrease in estrogens responsiveness and to hormonal therapy resistance. The effect on growth is correlated to the activation of MAPK/ERK and PI3K/Akt signaling pathways while the Hyal-induced down-regulation of ESR1 gene expression involves the activation of PI3K/Akt and NF-κB signaling pathways. Many of our data suggest that the effects of Hyal described here could be related to the activation of TLR signaling.

Taken together, our results demonstrate that the increase in HA degradation could be involved in breast cancer progression and in resistance to hormonal therapy.


13. Hyaluronan, inflammation, and breast cancer progression.
Kathryn L. Schwertfeger, Mary K. Cowman, Patrick G. Telmer, Eva A. Turley, James B. McCarthy, Front. Immunol., 08 June 2015.

Breast cancer-induced inflammation in the tumor reactive stroma supports invasion and malignant progression and is contributed to by a variety of host cells including macrophages and fibroblasts. Inflammation appears to be initiated by tumor cells and surrounding host fibroblasts that secrete pro-inflammatory cytokines and chemokines and remodel the extracellular matrix (ECM) to create a pro-inflammatory “cancerized” or tumor reactive microenvironment that supports tumor expansion and invasion. The tissue polysaccharide hyaluronan (HA) is an example of an ECM component within the cancerized microenvironment that promotes breast cancer progression. Like many ECM molecules, the function of native high-molecular weight HA is altered by fragmentation, which is promoted by oxygen/nitrogen free radicals and release of hyaluronidases within the tumor microenvironment. HA fragments are pro-inflammatory and activate signaling pathways that promote survival, migration, and invasion within both tumor and host cells through binding to HA receptors such as CD44 and RHAMM/HMMR.

In breast cancer, elevated HA in the peri-tumor stroma and increased HA receptor expression are prognostic for poor outcome and are associated with disease recurrence. This review addresses the critical issues regarding tumor-induced inflammation and its role within tumor reactive stroma as a key factor in malignant progression.


14. Targeting hyaluronic acid family for cancer chemoprevention and therapy.
Vinata B. Lokeshwar, Summan Mirza, Andre Jordan. Advances in Cancer Research, Volume 123, 2014, Pages 35-65

Hyaluronic acid or hyaluronan (HA) is perhaps one of the most uncomplicated large polymers that regulates several normal physiological processes and, at the same time, contributes to the manifestation of a variety of chronic and acute diseases, including cancer. Members of the HA signaling pathway (HA synthases, HA receptors, and HYAL-1 hyaluronidase) have been experimentally shown to promote tumor growth, metastasis, and angiogenesis, and hence each of them is a potential target for cancer therapy.

Furthermore, as these members are also overexpressed in a variety of carcinomas, targeting of the HA family is clinically relevant. A variety of targeted approaches have been developed to target various HA family members, including small-molecule inhibitors and antibody and vaccine therapies. These treatment approaches inhibit HA-mediated intracellular signaling that promotes tumor cell proliferation, motility, and invasion, as well as induction of endothelial cell functions. Being nontoxic, nonimmunogenic, and versatile for modifications, HA has been used in nanoparticle preparations for the targeted delivery of chemotherapy drugs and other anticancer compounds to tumor cells through interaction with cell-surface HA receptors. This review discusses basic and clinical translational aspects of targeting each HA family member and respective treatment approaches that have been described in the literature.



15. Caution urged with hyaluronic acid use.
April 1, 2019 Issue of McKnight's Long Term Care News

A small study has found inflammatory lesions worsen with the use of topical hyaluronic acid, and the solution can cause wound deterioration in residents with conditions such as scleroderma. Italian researchers followed 79 patients with 106 ulcers, whose wounds did not respond to typical wound dressings. They were then treated with four different HA-based products already on the market. While just over half of the wounds healed without side effects, more than one-third of patients developed erythema or pain and saw their wounds grow.

“Hyaluronic acid in wound dressings has certainly helped to expand the therapeutic arsenal in the context of wound care,” the team reported in the March issue of Wounds. “However, like any innovation, HA must be placed in the right context … Clinicians must be aware that this glycosaminoglycan plays a role in the pathogenesis of some diseases.” In sclerodermic skin, chronic inflammation affects the connecting tissue and leads to progressive fibrosis, and patients with scleroderma overproduce hyaluronan, collagen and fibronectin. Researchers discouraged broad-scale HA use.


16. Review of long-term adverse effects associated with the use of chemically-modified animal and nonanimal source hyaluronic acid dermal fillers.
Edwards PC1, Fantasia JE. Clin Interv Aging. 2007;2(4):509-19

Although only recently introduced, chemically-modified hyaluronic acid dermal fillers have gained widespread acceptance as "redefining" dermal fillers in the fields of dermatology and cosmetic facial surgery. Although hyaluronic acid-based dermal fillers have a low overall incidence of long-term side effects, occasional adverse outcomes, ranging from chronic lymphoplasmacytic inflammatory reactions to classic foreign body-type granulomatous reactions have been documented. These long-term adverse events are reviewed.


17. Perils of dermal fillers.
Colbert SD, Southorn BJ, Brennan PA, Ilankovan V., Br Dent J. 2013 Apr;214(7):339-40.

With the increasing use of hyaluronic acid-based injectable fillers for cosmetic enhancement a variety of adverse reactions are being reported in the literature.

Although most adverse outcomes occur early we describe an interesting case study of a female presenting with granulomatous complications ten years postoperatively. To our knowledge this is one of the longest reported delayed reactions. For the general dental practitioner offering such treatments it is important to be fully aware of the potential risks and how they may be managed in order to consent appropriately for cosmetic procedures.



18. Caution should be used in long-term treatment with oral compounds of hyaluronic acid in patients with a history of cancer.
Simone P,Alberto M, Clin Drug Investig. 2015 Nov;35(11):689-92.

Intra-articular administration of hyaluronic acid is a valuable therapeutic tool for the management of patients with osteoarthritis. However, in recent years numerous formulations containing hyaluronic acid administrable by oral route have entered the market. Even if there are some data in the literature that have shown their effectiveness, systemic administration may expose a greater risk in certain situations. In fact, although hyaluronic acid is not considered a drug it is certain that it can interact with specific receptors and promote cell proliferation. This interaction may be potentially hazardous in cancer patients for which these oral formulations should be contraindicated.



19. The Roles of Hyaluronan/RHAMM/CD44 and Their Respective Interactions along the Insidious Pathways of Fibrosarcoma Progression
Nikitovic, D., Kouvidi, K., Karamanos, N. K., & Tzanakakis, G. N. (2013). BioMed research international, 2013.

Fibrosarcomas are rare malignant mesenchymal tumors originating from fibroblasts. Importantly, fibrosarcoma cells were shown to have a high content and turnover of extracellular matrix (ECM) components including hyaluronan (HA), proteoglycans, collagens, fibronectin, and laminin. ECMs are complicated structures that surround and support cells within tissues. During cancer progression, significant changes can be observed in the structural and mechanical properties of the ECM components. Importantly, hyaluronan deposition is usually higher in malignant tumors as compared to benign tissues, predicting tumor progression in some tumor types. Furthermore, activated stromal cells are able to produce tissue structure rich in hyaluronan in order to promote tumor growth. Key biological roles of HA result from its interactions with its specific CD44 and RHAMM (receptor for HA-mediated motility) cell-surface receptors. HA-receptor downstream signaling pathways regulate in turn cellular processes implicated in tumorigenesis. Growth factors, including PDGF-BB, TGF?2, and FGF-2, enhanced hyaluronan deposition to ECM and modulated HA-receptor expression in fibrosarcoma cells. Indeed, FGF-2 through upregulation of specific HAS isoforms and hyaluronan synthesis regulated secretion and net hyaluronan deposition to the fibrosarcoma pericellular matrix modulating these cells’ migration capability. In this paper we discuss the involvement of hyaluronan/RHAMM/CD44 mediated signaling in the insidious pathways of fibrosarcoma progression.



20. bFGF induces changes in hyaluronan synthase and hyaluronidase isoform expression and modulates the migration capacity of fibrosarcoma cells
Berdiaki, A., Nikitovic, D., Tsatsakis, A., Katonis, P., Karamanos, N. K., & Tzanakakis, G. N.
(2009). Biochimica et Biophysica Acta (BBA)-General Subjects, 1790(10), 1258-1265.

Hyaluronan (HA) a glycosaminoglycan, is capable of transmitting extracellular matrix derived signals to regulate cellular functions. In this study, we investigated whether the changes in HT1080 and B6FS fibrosarcoma cell lines HA metabolism induced by basic fibroblast growth factor (bFGF) are correlated to their migration. bFGF inhibited the degradation of HA by decreasing hyaluronidase-2 expression in HT1080 cells (p=0.0028), increased HA-synthase-1 and -2 expression as we previously found and enhanced high molecular weight HA deposition in the pericellular matrix. Increased endogenous HA production (p=0.0022) and treatment with exogenous high molecular weight HA (p=0.0268) correlated with a significant decrease of HT1080 cell migration capacity. Transfection with siHAS2 and siHAS1 showed that mainly HAS1 synthesized high molecular weight HA regulates HT1080 cell motility. Induced degradation of the HA content by hyaluronidase treatment and addition of low molecular weight HA, resulted in a significant stimulation of HT1080 cells' motility (p<0.01). In contrast, no effects on B6FS fibrosarcoma cell motility were observed. bFGF regulates, in a cell-specific manner the migration capability of fibrosarcoma cells by modulating their HA metabolism. HA metabolism is suggested to be a potential therapeutic target in fibrosarcoma.



21. Silencing of hyaluronan synthase 2 suppresses the malignant phenotype of invasive breast cancer cells.
Li, Y., Li, L., Brown, T. J., & Heldin, P. (2007).

Accumulation of hyaluronan has been demonstrated in the peritumoral breast cancer stroma and nests of tumor cells. In this study, we have quantified the production of hyaluronan and the expression of mRNAs encoding hyaluronan synthesizing (HAS) and hyaluronan degrading (HYAL) enzymes in a panel of breast cancer cell lines. The analysis revealed that highly invasive breast cancer cells produce high amounts of hyaluronan and express preferentially HAS2 mRNA, whereas less invasive breast cancer cells produce low amount of hyaluronan and express HAS1 and HYAL1 mRNAs. We explored the importance of HAS2 expression for breast cancer tumorigenicity, by specifically silencing the HAS2 gene using RNA interference (RNAi)-mediated suppression in the invasive breast cancer cell line Hs578T. This led to a less aggressive phenotype of the breast tumor cells, as assessed by cell growth, both in anchorage-dependent and anchorage-independent cultures. siRNA-mediated knock down of HAS2 in Hs578T breast tumor cells led to an up-regulation of HAS1, HAS3 and HYAL1 mRNAs, resulting in only a 50% decrease in the net hyaluronan production; however, the synthesized hyaluronan was of lower size and more polydisparse compared to control siRNA-treated cells. Interestingly, Hs578T cells deprived of HAS2 migrated only half as efficiently as HAS2 expressing cells through cell-free areas in a culture wounding assay and through Transwell polycarbonate membrane as well as invaded a Matrigel layer. These results imply that alterations in HAS2 expression and endogenously synthesized hyaluronan affect the malignant phenotype of Hs578T breast cancer cells.



22. Antisense-Mediated Suppression of Hyaluronan Synthase 2 Inhibits the Tumorigenesis and Progression of Breast Cancer
Udabage L, Brownlee GR, Waltham M, Blick T, Walker EC, Heldin P, Nilsson SK, Thompson EW, Brown TJ. Cancer Res. 2005 Jul 15;65(14):6139-50.

The progression of several cancers is correlated with the increased synthesis of the glycosaminoglycan, hyaluronan. Hyaluronan is synthesized at the plasma membrane by various isoforms of hyaluronan synthases (HAS). The importance of HAS2 expression in highly invasive breast cancer was characterized by the antisense inhibition of HAS2 (ASHAS2). The effect of HAS2 inhibition on cell proliferation, migration, hyaluronan metabolism, and receptor status was characterized in vitro, whereas the effect on tumorigenicity and metastasis was established in vivo. HAS2 inhibition resulted in a 24-hour lag in proliferation that was concomitant to transient arrest of 79% of the cell population in G0-G1. Inhibition of HAS2 did not alter the expression of the other HAS isoforms, whereas hyaluronidase (HYAL2) and the hyaluronan receptor, CD44, were significantly down-regulated. ASHAS2 cells accumulated greater amounts of high molecular weight hyaluronan (>10,000 kDa) in the culture medium, whereas mock and parental cells liberated less hyaluronan of three distinct molecular weights (100, 400, and 3,000 kDa). The inhibition of HAS2 in the highly invasive MDA-MB-231 breast cancer cell line inhibited the initiation and progression of primary and secondary tumor formation following s.c. and intracardiac inoculation into nude mice, whereas controls readily established both primary and secondary tumors. The lack of primary and secondary tumor formation was manifested by increased survival times where ASHAS2 animals survived 172% longer than the control animals. Collectively, these unique results strongly implicate the central role of HAS2 in the initiation and progression of breast cancer, potentially highlighting the co-dependency between HAS2, CD44, and HYAL2 expression.



23. Spontaneous Metastasis of Prostate Cancer Is Promoted by Excess Hyaluronan Synthesis and Processing
Bharadwaj, A. G., Kovar, J. L., Loughman, E., Elowsky, C., Oakley, G. G., & Simpson, M. A. (2009). The American journal of pathology, 174(3), 1027-1036. 2009

Accumulation of extracellular hyaluronan (HA) and its processing enzyme, the hyaluronidase Hyal1, predicts invasive, metastatic progression of human prostate cancer. To dissect the roles of hyaluronan synthases (HAS) and Hyal1 in tumorigenesis and metastasis, we selected nonmetastatic 22Rv1 prostate tumor cells that overexpress HAS2, HAS3, or Hyal1 individually, and compared these cells with co-transfectants expressing Hyal1 + HAS2 or Hyal1 + HAS3. Cells expressing only HAS were less tumorigenic than vector control transfectants on orthotopic injection into mice. In contrast, cells co-expressing Hyal1 + HAS2 or Hyal1 + HAS3 showed greater than sixfold and twofold increases in tumorigenesis, respectively. Fluorescence and histological quantification revealed spontaneous lymph node metastasis in all Hyal1 transfectant-implanted mice, and node burden increased an additional twofold when Hyal1 and HAS were co-expressed. Cells only expressing HAS were not metastatic. Thus, excess HA synthesis and processing in concert accelerate the acquisition of a metastatic phenotype by prostate tumor cells. Intratumoral vascularity did not correlate with either tumor size or metastatic potential. Analysis of cell cycle progression revealed shortened doubling times of Hyal1-expressing cells. Both adhesion and motility on extracellular matrix were diminished in HA-overproducing cells; however, motility was increased twofold by Hyal1 expression and fourfold to sixfold by Hyal1/HAS co-expression, in close agreement with observed metastatic potential. This is the first comprehensive examination of these enzymes in a relevant prostate cancer microenvironment.



24. Hyaluronan: Towards novel anti-cancer therapeutics
Karbownik, M. S., & Nowak, J. Z. (2013). Pharmacological Reports, 65(5), 1056-1074.

The understanding of the role of hyaluronan in physiology and various pathological conditions has changed since the complex nature of its synthesis, degradation and interactions with diverse binding proteins was revealed. Initially perceived only as an inert component of connective tissue, it is now known to be involved in multiple signaling pathways, including those involved in cancer pathogenesis and progression. Hyaluronan presents a mixture of various length polymer molecules from finely fragmented oligosaccharides, polymers intermediate in size, to huge aggregates of high molecular weight hyaluronan. While large molecules promote tissue integrity and quiescence, the generation of breakdown products enhances signaling transduction, contributing to the pro-oncogenic behavior of cancer cells. Low molecular weight hyaluronan has well-established angiogenic properties, while the smallest hyaluronan oligomers may counteract tumor development. These equivocal properties make the role of hyaluronan in cancer biology very complex. This review surveys recent data on hyaluronan biosynthesis, metabolism, and interactions with its binding proteins called hyaladherins (CD44, RHAMM), providing the molecular background underlying its differentiated biological activity. In particular, the article critically presents current ideas on actual role of hyaluronan in cancer. The paper additionally maps a path towards promising novel anti-cancer therapeutics which target hyaluronan metabolic enzymes and hyaladherins, and constitute hyaluronan-based drug delivery systems.