Hyaluronan and Tumor Growth

Abstract

The study published in this issue of The American Journal of Pathology by Simpson et al 1 adds a new dimension to the role of hyaluronan in cancer by demonstrating that inhibition of endogenous hyaluronan synthesis dramatically reduces tumor growth in vivo. In previous studies, these investigators showed that aggressive PC3M-LN4 human prostate carcinoma cells contain two of the three synthases that synthesize hyaluronan, namely HAS2 and HAS3, and that transfectants of PC3M-LN4 with antisense to HAS2 and HAS3 mRNA synthesized significantly less hyaluronan. 2,3 In the present study, stable transfectants with antisense-HAS2 and antisense-HAS3 were used alone or in combination to study tumor growth after subcutaneous injection in immunocompromised mice. The antisense-HAS transfectants produced tumors that were three to four times smaller than control tumors after 3 weeks. Although inhibition of hyaluronan synthesis reduced rates of cell proliferation in culture, the antisense-HAS transfectant tumors contained similar proportions of dividing and apoptopic cells as did the control tumors at 3 weeks. This finding suggests that the reduced size of the antisense-HAS transfectant tumors is due to reduced rates of growth early in development of the tumor. The authors also found that blood vessel density was diminished by 70 to 80%, implying that hyaluronan levels may be an important determinant of vascularity, and that this rather than proliferation is the predominant factor in the effect of hyaluronan on tumor growth in this model. Interestingly, inclusion of exogenous hyaluronan with the initial injection of the transfected tumor cells restored levels of tumor growth and vascularity to those seen in control tumors, suggesting that early angiogenic events may be crucial.Numerous other studies have demonstrated a close correlation between tumor progression and hyaluronan production, either by tumor cells themselves or by stromal cells associated with tumors. This correlation has been observed in cell culture, in experimental animal models, and in human patients. In fact, recent work shows that hyaluronan content correlates with increased progression in several cancers, including breast, ovarian, prostate, and colorectal cancers. 4,5 In addition to the observation that hyaluronan is present in elevated amounts in numerous types of tumors, experimental manipulations of hyaluronan levels and interactions suggest a vital role for hyaluronan in promoting malignant cell behavior in vitro and in vivo. For example, experimental elevation of hyaluronan production in HT1080 human fibrosarcoma cells or TSU human prostate carcinoma cells enhances growth in vivo. 6,7 Also, low producers of hyaluronan selected from a population of mammary carcinoma cells are less metastatic than high producers, and metastatic capacity was restored to the low producers by elevating their hyaluronan production. 8 Hyaluronan-Receptor InteractionsHyaluronan interacts with several cell surface receptors, including CD44, RHAMM, LYVE-1, HARE, layilin, and Toll...

Identification and Analysis of the Promoter Region of the Human Hyaluronan Synthase 2 Gene

“…HA has been implicated in chondrogenesis and cartilage homeostasis, embryonic development, immunomodulation, wound healing, and a variety of disease processes, including arthritis, malignancies, and pulmonary and vascular disease, together with other immune and inflammatory disorders (27)(28)(29)(30)(31)(32)(33)(34)(35). In addition, the transcriptional regulation of HAS2 has potential significance in renal fibrosis (10 -12), diabetic nephropathy (13), and peritoneal inflammation (16).…”

Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

“…Among such molecules are matrix hyaluronan (HA) (2,3) and its cell surface receptor, CD44 (4). HA is a major component of the ECM and is significantly enriched in many types of tumors (5). CD44 is a multifunctional transmembrane glycoprotein expressed in HNSCC cells and carcinoma tissues (6,7).…”

CD44-dependent Intracellular and Extracellular Catabolism of Hyaluronic Acid by Hyaluronidase-1 and -2

“…Despite the simplicity of its composition, HA has a great number of biological functions. It not only functions as a biological glue that participates in lubricating joints or holding together gel-like connective tissues, but also functions as a microenvironmental cue that co-regulates cell behavior during embryonic development and morphogenesis (1,2), wound healing (3,4), repair and regeneration, inflammation (5-7), and tumor progression and invasion (8,9).…”