Stromal and Epithelial Expression of Tumor Markers Hyaluronic Acid and HYAL1 Hyaluronidase in Prostate Cancer

Lokeshwar, Vinata B.; Rubinowicz, Diego; Schroeder, G.; Forgács, Éva; Minna, John D.; Block, Norman L.; Nadji, Mehrdad; Lokeshwar, Bal L.

doi:10.1074/jbc.m008432200

Cited by 284 publications

(334 citation statements)

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“…It has been concluded from these studies that hyaluronidase-mediated degradation of tumor hyaluronan gener-ates high levels of hyaluronan oligosaccharides which, in turn, stimulate tumor angiogenesis and consequently tumor growth. 29,30 This postulate is supported by a recent study indicating that increased hyaluronan expression in glioma cells that do not express hyaluronidase does not stimulate tumor progression. 31 However, hyaluronan oligosaccharides have also been shown to inhibit tumor growth in vivo.…”

Section: Hyaluronan In Angiogenesissupporting

confidence: 72%

Hyaluronan and Tumor Growth

Toole

Hascall

2002

The American Journal of Pathology

113

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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...

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Section: Hyaluronan In Angiogenesissupporting

confidence: 72%

Hyaluronan and Tumor Growth

Toole

Hascall

2002

The American Journal of Pathology

113

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“…This possibility certainly exists considering that CD44 has previously been implicated in facilitating PCa cell invasion in vitro (e.g. Lokeshwar et al, 1995;Draffin et al, 2004;Omara-Opyene et al, 2004). In this regard, it is of interest to note that the LAPC-9 tumors, which were initially isolated from a bony metastasis, contain many more CD44 þ cells than LAPC-4 tumors, which were originally isolated from a lymph node metastasis.…”

Section: Discussionmentioning

confidence: 98%

“…Furthermore, although CD44 expression is reported to be reduced in metastases (Nagabhushan et al, 1996;De Marzo et al, 1998;Noordzij et al, 1999), the CD44 þ PCa cells are found to predominate in two visceral metastases (Liu et al, 1999). Similar to expression studies, the potential role of CD44 in PCa development and metastases is controversial -although some studies show a tumor-suppressive function of CD44 in overexpression experiments (Gao et al, 1997(Gao et al, , 1998, many other studies implicate CD44 in PCa cell proliferation, adhesion, migration, and invasion in vitro as well as in metastatic dissemination in vivo (Lokeshwar et al, 1995;Paradis et al, 1998;Liu et al, 1999;Draffin et al, 2004;Omara-Opyene et al, 2004). Many studies mentioned above utilize either human tissues to carry out correlative immunohistochemistry (IHC) or bulk-cultured PCa cells to carry out overexpression experiments and the key experiment of using purified CD44 þ and CD44 À cells from the same culture or tumor to compare their potentially different biological and tumorigenic properties has not yet been done.…”

Section: Introductionmentioning

confidence: 88%

Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells

et al. 2006

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CD44 is a multifunctional protein involved in cell adhesion and signaling. The role of CD44 in prostate cancer (PCa) development and progression is controversial with studies showing both tumor-promoting and tumor-inhibiting effects. Most of these studies have used bulk-cultured PCa cells or PCa tissues to carry out correlative or overexpression experiments. The key experiment using prospectively purified cells has not been carried out. Here we use FACS to obtain homogeneous CD44 þ and CD44 À tumor cell populations from multiple PCa cell cultures as well as four xenograft tumors to compare their in vitro and in vivo tumor-associated properties. Our results reveal that the CD44 þ PCa cells are more proliferative, clonogenic, tumorigenic, and metastatic than the isogenic CD44 À PCa cells. Subsequent molecular studies demonstrate that the CD44 þ PCa cells possess certain intrinsic properties of progenitor cells. First, BrdU pulse-chase experiments reveal that CD44 þ cells colocalize with a population of intermediate label-retaining cells. Second, CD44 þ PCa cells express higher mRNA levels of several 'stemness' genes including Oct-3/4, Bmi, b-catenin, and SMO. Third, CD44 þ PCa cells can generate CD44 À cells in vitro and in vivo. Fourth, CD44 þ PCa cells, which are AR À , can differentiate into AR þ tumor cells. Finally, a very small percentage of CD44 þ PCa cells appear to undergo asymmetric cell division in clonal analyses. Altogether, our results suggest that the CD44 þ PCa cell population is enriched in tumorigenic and metastatic progenitor cells.

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“…12,20,21,46 Macrophages, which accumulate inside and around prostate tumors, in turn secrete IL-1␤ and tumor necrosis factor-␣, 20 factors known to increase HA synthesis, 32 and cancer-associated fibroblasts produce HA. 36 Prostate cancers are hypoxic; hypoxia makes tumors more aggressive, 47 and hypoxia stimulates HA synthesis. 48 Multiple mechanisms consequently may explain why HA is increased in prostate tumors and their surroundings, and why the magnitude of this is linked to disease aggressiveness.…”

Section: Discussionmentioning

confidence: 99%

Prostate Cancer Increases Hyaluronan in Surrounding Nonmalignant Stroma, and This Response Is Associated with Tumor Growth and an Unfavorable Outcome

Josefsson

Adamo

Hammarsten

et al. 2011

The American Journal of Pathology

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Our objective was to investigate whether the presence of a tumor increases hyaluronan (HA) levels in surrounding prostate tissues and whether this extratumoral HA influences tumor growth and outcome. From a series of 287 men diagnosed with prostate cancer at transurethral resection and followed up with watchful waiting, tissue microarrays were constructed, stained, and scored for HA. A high HA staining score in the tumor stroma or in nonmalignant prostate tissue stroma were both associated positively with higher Gleason score and larger tumor volume, and was associated with a poor outcome. HA staining score was not an independent marker for outcome (multivariate Cox, with Gleason score, tumor volume, stage, and HA variables). In an orthotopic rat prostate cancer model, hyaluronic acid synthase-1 mRNA levels and HA staining were increased in normal prostate tissue surrounding prostate cancer. Orthotopic prostate cancer growth was increased by intraprostatic injection of HA. In conclusion, cancer in the prostate apparently stimulates HA synthesis both in tumor stroma and in the surrounding normal tissue. This promoted tumor growth and was associated with an unfavorable outcome. (Am J Pathol

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Stromal and Epithelial Expression of Tumor Markers Hyaluronic Acid and HYAL1 Hyaluronidase in Prostate Cancer

Cited by 284 publications

References 60 publications

Hyaluronan and Tumor Growth

Hyaluronan and Tumor Growth

Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells

Prostate Cancer Increases Hyaluronan in Surrounding Nonmalignant Stroma, and This Response Is Associated with Tumor Growth and an Unfavorable Outcome

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