Low molecular weight hyaluronan inhibits colorectal carcinoma growth by decreasing tumor cell proliferation and stimulating immune response

Alaniz, Laura; Rizzo, Miguel; Malvicini, Mariana; Jaunarena, Jorge; Avella, Diego M.; Atorrasagasti, Catalina; Aquino, Jorge B.; Garcı́a, Mariana; Matar, Pablo; Silva, Marcelo; Mazzolini, G.

doi:10.1016/j.canlet.2008.12.029

Cited by 54 publications

(40 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whilst HA fragments in the 30-50 disaccharide range have been shown to be angiogenic [65], smaller HA fragments have been shown to inhibit tumor growth [43][44][45] and block the formation of a pericellular matrix formation around chondrocytes [48,49]. Small HA oligomers in the 6-10 disaccharides range appear to have unique biological properties and can also inhibit a variety of tumors in vitro and in vivo [43,44,[66][67][68][69]. Ghatak et al [44] have demonstrated that HA oligomers can inhibit PI 3-kinase activity and phosphorylation of Akt and stimulate the expression of PTEN, a phosphatase which degrades the major signaling product of PI 3-kinase action, phosphoinositide 3,4,5-trisphosphate.…”

Section: Discussionmentioning

confidence: 99%

Versican induces a pro-metastatic ovarian cancer cell behavior which can be inhibited by small hyaluronan oligosaccharides

Ween

Hummitzsch

Rodgers

et al. 2010

Clin Exp Metastasis

View full text Add to dashboard Cite

The assembly of pericellular matrix containing hyaluronan (HA) and versican has been shown to be a pre-requisite for proliferation and migration of mesenchymal cells. In this study, we investigated whether treatment with recombinant versican could induce the formation of a pericellular matrix by ovarian cancer cells (OVCAR-3, OVCAR-5, and SKOV-3) and promote their motility, invasion, and adhesion to peritoneal cells in vitro. We also determined whether versican-induced pericellular matrix formation and metastatic cancer cell behavior could be blocked by small HA oligosaccharides. Only combined treatment with recombinant versican and HA resulted in pericellular matrix formation by OVCAR-5 and SKOV-3 but not by OVCAR-3 cells, which lack the HA receptor, CD44. The motility of OVCAR-5 and SKOV-3 cells was significantly increased in scratch wound and chemotaxis assays following treatment with recombinant versican and HA. Versican and HA also promoted invasion of SKOV-3 and OVCAR-5 cells but had no effect on OVCAR-3 cells. We have demonstrated that exogenous HA significantly increased OVCAR-5 and SKOV-3 adhesion to peritoneal cells but adhesion was not further increased by versican treatment. Small HA oligomers (6-10 disaccharides) were able to significantly block formation of pericellular matrix by OVCAR-5 cells, as well as the increased motility and invasion induced by recombinant versican. HA oligomers also significantly blocked OVCAR-5 adhesion to peritoneal cells both in the presence and absence of exogenous HA. The dependence of CD44 for the versican and HA mediated effects were demonstrated by the inhibition of pericellular matrix formation as well as motility and invasion of OVCAR-5 cells following treatment with CD44 neutralizing antibody in the presence of versican and HA. We conclude that the acquisition of a HA/versican pericellular matrix by ovarian cancer cells increases their metastatic potential. HA oligomers can block this mechanism and are promising inhibitors of ovarian cancer dissemination.

show abstract

Section: Discussionmentioning

confidence: 99%

Versican induces a pro-metastatic ovarian cancer cell behavior which can be inhibited by small hyaluronan oligosaccharides

Ween

Hummitzsch

Rodgers

et al. 2010

Clin Exp Metastasis

View full text Add to dashboard Cite

show abstract

“…Was Modulated in Co-culture-Stromal HAS2 is known to play a role in the recruitment of tumor-associated macrophages (39), and low molecular weight HA increases the number of CD3 ϩ lymphocytes in a murine colorectal carcinoma model (40). Therefore, we analyzed whether other chemoattractants are modulated by the interaction of KYSE-410 cells and SF.…”

Section: Secretion Of Chemokines Ccl5 and Ccl11 By Fibroblastsmentioning

confidence: 99%

“…CCL5 recruits mainly T lymphocytes and monocytes into the tumor (41). Also, HA is important for macrophage recruitment (39,54), and low molecular weight HA leads to increased numbers of CD3 ϩ lymphocytes (40). Low molecular weight HA can induce chemokine and cytokine expression of macrophages and act as an adjuvant to enhance the T cell response (50,55,56).…”

Section: Journal Of Biological Chemistry 4101mentioning

confidence: 99%

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

Kretschmer

Freudenberger

Twarock

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

The aim of this study was to characterize the interaction of KYSE-410, an esophageal squamous cell carcinoma cell line, and fibroblasts with respect to the extracellular matrix component hyaluronan (HA) and chemokine expression. KYSE-410 cells induced the mRNA expression of HA synthase 2 (Has2) in normal skin fibroblasts (SF) only in direct co-cultures. Parallel to Has2 mRNA, Has2 antisense RNA (Has2os2) was up-regulated in co-cultures. Knockdown of LEF1, a downstream target of Wnt signaling, abrogated Has2 and Has2os2 induction. After knockdown of Has2 in SF, significantly less ␣-smooth muscle actin expression was detected in co-cultures. Moreover, it was investigated whether the phenotype of KYSE-410 was affected in co-culture with SF and whether Has2 knockdown in SF had an impact on KYSE-410 cells in co-culture. However, no effects on epithelial-mesenchymal transition markers, proliferation, and migration were detected. In addition to Has2 mRNA, the chemokine CCL5 was up-regulated and CCL11 was down-regulated in SF in co-culture. Furthermore, co-cultures of KYSE-410 cells and cancer-associated fibroblasts (CAF) were investigated. Similar to SF, Has2 and Ccl5 were up-regulated and Ccl11 was down-regulated in CAF in co-culture. Importantly and in contrast to SF, inhibiting HA synthesis by 4-methylumbelliferone abrogated the effect of co-culture on Ccl5 in CAF. Moreover, HA was found to promote adhesion of CD4 ؉ but not CD8 ؉ cells to xenogaft tumor tissues. In conclusion, direct co-culture of esophageal squamous cell carcinoma and fibroblasts induced stromal HA synthesis via Wnt/LEF1 and altered the chemokine profile of stromal fibroblasts, which in turn may affect the tumor immune response.

show abstract

“…However, it is not known from the results of this study whether the enzymes resulting in synthesis or degradation are involved in generating and maintaining the observed HA polymer sizes. Nevertheless, HA polymers of different sizes have a vast array of functions (Kikuchi et al 1996, Watanabe & Yamaguchi 1996, Ghosh & Guidolin 2002, Alaniz et al 2009). Smaller HA fragments (200-2000 kDa) are involved in a variety of normal and pathological processes (Stern et al 2006); they also come in sizes that overlap in the functions that they perform.…”

Section: Discussionmentioning

confidence: 99%

“…HA is synthesized by a class of integral membrane proteins called HA synthases (Watanabe & Yamaguchi 1996), and is degraded by a family of enzymes called hyaluronidases (Obara et al 2001) resulting in different molecular weight fragments which may exhibit different properties (Kikuchi et al 1996, Ghosh & Guidolin 2002, Alaniz et al 2009). Low-molecular weight HA fragments have been reported to induce cytokines and chemokines that are implicated in inflammation and degradation of ECM (Noble et al 1996).…”

Section: Introductionmentioning

confidence: 99%

Hyaluronan (HA) content, the ratio of HA fragments and the expression of CD44 in the ovine cervix vary with the stage of the oestrous cycle

Perry¹,

Haresign²,

Wathes³

et al. 2010

Reproduction

View full text Add to dashboard Cite

The complex anatomy of the ovine cervix limits the success of trans-cervical artificial insemination in sheep. However, there is a degree of natural relaxation of cervix at oestrus that is accompanied by an increase in the water content. As hyaluronan (HA) has a high affinity for water molecules, in this study, we tested the hypothesis that the HA content of the cervix, the proportion of different size fragments of HA and expression of its receptor CD44 vary with the stage of the oestrous cycle. Oestrous was synchronized in 25 Welsh mountain ewes, and their cervices were collected either during luteal phase (nZ8) or pre-LH (nZ8) or post-LH (nZ9) surge stage of the oestrous cycle. The pre-LH surge group had the highest HA content (2.96 ng/mg of cervical tissue), which was significantly (P%0.05) higher than that observed for the post-LH surge (2.04 ng/mg) group. The luteal phase group had a mean HA content intermediate between the pre-and post-LH surge groups, and was significantly different from either. The frequency of cervical samples containing both sizes of HA fragments (small and large) was significantly higher (P%0.05) in the pre-LH surge group compared with the luteal and the post-LH surge groups, whereas that in post-LH surge group was significantly (P%0.05) higher than that in the luteal group. The number of cervical samples that contained only small HA fragments was significantly (P%0.05) higher in the luteal group compared with both the pre-and post-LH surge groups, whereas the number of samples containing only large HA fragments was significantly (P%0.05) higher in the post-LH surge group compared with the luteal or pre-LH surge groups. Overall mean expression of CD44 in the vaginal and mid regions was significantly (P%0.001) higher than that in the uterine region, with no difference between the vaginal and mid regions of the cervix. Pattern of CD44 expression depended on the stage of the oestrous cycle. At the luteal stage, CD44 expression did not vary among epithelial, sub-epithelial, circular and longitudinal smooth muscle layers, whereas at the pre-and post-LH surge stages, the expression in the epithelial layer was significantly (P%0.001) higher than that in the other three layers. In general, CD44 expression in the transverse smooth muscle layer was significantly (P%0.05) lower than the expression in all the other layers at all the stages of the oestrous cycle. The results indicated that the HA varied with the steroid status. Higher HA values at a time when cervical relaxation is naturally higher may indicate its involvement in remodelling of the cervix at oestrus.

show abstract

Low molecular weight hyaluronan inhibits colorectal carcinoma growth by decreasing tumor cell proliferation and stimulating immune response

Cited by 54 publications

References 34 publications

Versican induces a pro-metastatic ovarian cancer cell behavior which can be inhibited by small hyaluronan oligosaccharides

Versican induces a pro-metastatic ovarian cancer cell behavior which can be inhibited by small hyaluronan oligosaccharides

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

Hyaluronan (HA) content, the ratio of HA fragments and the expression of CD44 in the ovine cervix vary with the stage of the oestrous cycle

Contact Info

Product

Resources

About