What is Hyaluronan?

Hyaluronan (HA) is a megadalton polymeric glycosaminoglycan made up of repeating disaccharide subunits of N-acetylglucosamine and glucuronic acid. It is found in most tissues and body fluids of vertebrates, but is most abundant in the extracellular matrix of connective tissues. High concentrations of HA can be found in tissues, such as the skin, umbilical cord, synovial fluid and vitreous humour. HA is rapidly turned over in normal skin with a half-life of less than two days, but relatively constant levels are maintained by similar rates of synthesis and degradation.

HA in the Tumor Microenvironment

The tumor microenvironment (TME) includes the malignant cancer cells as well as the many non-malignant cells within a tumor (for example fibroblasts and immune cells), blood vessels, and extracellular matrix components, such as collagen and hyaluronan (HA).

The cancer cells within the tumor can recruit other cell types into the TME and then stimulate them to generate growth factors, signaling molecules and other matrix components that can further optimize the TME for malignant cell growth and result in an immunosuppressive microenvironment. The cancer cell survival can depend on the specialized TME that is assembled for optimal growth and metastasis, so perturbation of the TME may lead to a less favorable microenvironment for tumor growth.

Decades of investigation have led to the current mechanism-based hypothesis for the role of HA in the TME. Accumulation of HA and associated water within some solid tumors can lead to increased pressure within the tumor microenvironment. The increased pressure can lead to blood vessel compression restricting blood flow, leading to increased areas of hypoxia, and impeding access of therapeutic intervention into the tumor.

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What is HA-High Cancer?

HA-High cancer is disease that can be characterized directly by the detection of HA in a tumor specimen. Preclinical models have shown that accumulation of HA in the tumor microenvironment is associated with increased tumor pressure and poor perfusion of tumor tissue. High levels of HA in tumors have been correlated with decreased survival in several tumor types with increased interstitial pressure including pancreatic ductal adenocarcinoma,1 non-small cell lung,2 gastric3 and metastatic breast cancers.4 Additional tumor types that have been associated with high-levels of HA include prostate, bladder, mesothelioma, colon and ovarian cancers.These cancers are sometimes also characterized by robust desmoplastic reactions (increased infiltration of fibroblasts and growth of fibrous tissue in and around the tumor) that result in a fibroblast-rich dense HA-High extracellular matrix within the tumor microenvironment. The HA in the tumor microenvironment binds large amounts of water increasing the volume of the HA gel-like fluid within the tumor leading to increased pressure, blood vessel compression and decreased perfusion. Additional effects of HA accumulation in tumors may include increased areas of hypoxia (low oxygen content) in the tumor microenvironment, decreased immune cell function, and increased resistance to anti-cancer therapies presumably due to decreased drug delivery.

1Whatcott et al. Clin Cancer Res. 21:15 (2015)
2 Pirinen et al. Int J Cancer 95:12 (2001)
3 Setala et al. Br J Cancer 79:1133 (1999)
4 Auvinen et al. Am J Pathol. 156:529 (2000)
5 Jacobetz et al., Gut 2013, 62:112

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