Molecular characterization of kidney cancer: association of hyaluronic acid family with histological subtypes and metastasis.

Department of Urology, University of Miami School of Medicine, Miami, Florida 33101, USA.
Cancer (Impact Factor: 5.2). 09/2011; 118(9):2394-402. DOI: 10.1002/cncr.26520
Source: PubMed

ABSTRACT Molecular profiling of renal cell carcinomas (RCCs) may improve the distinction between oncocytoma and malignant RCC subtypes and aid in early detection of metastasis. The hyaluronic acid (HA) family includes HA synthases (HAS1, HAS2, HAS3), hyaluronidases (HYAL-1, HYAL-2, HYAL-3, HYAL-4, PH20, HYAL-P1), and HA receptors (CD44s, CD44v, RHAMM). HA family members promote tumor growth and metastasis. The authors evaluated the expression of HA family members in kidney specimens.
By using quantitative polymerase chain reaction, mRNA levels of 12 HA family members were measured in tumor specimens obtained from 86 consecutive patients undergoing nephrectomy; 80 of them also provided normal specimens. Mean and median follow-up were 15.2 ± 8.8 and 13.8 months. RCC specimens included clear cell RCC: 65; papillary: 10; chromophobe: 5; oncocytoma: 6; metastasis positive: 17.
Median HAS1, CD44s, and RHAMM transcript levels were elevated 3- to 25-fold in clear cell RCC and papillary and chromophobe tumors when compared with normal tissues. HYAL-4, CD44s, and RHAMM levels were elevated 4- to 12-fold in clear cell RCC and papillary tumors when compared with oncocytomas; only HYAL-4 levels distinguished between chromophobe and oncocytoma (P = .009). CD44s and RHAMM levels were significantly higher in tumors <4 cm (510 ± 611 and 19.6 ± 20.8, respectively) when compared with oncocytoma (46.4 ± 20 and 3.8 ± 2.5; P ≤ .006). In univariate and multivariate analyses, CD44s (P < .0001), RHAMM (P < .0001), stage, tumor size, and/or renal vein involvement were significantly associated with metastasis. The combined CD44s + RHAMM marker had 82% sensitivity and 86% specificity to predict metastasis.
CD44s and RHAMM levels distinguish between oncocytoma and RCC subtypes regardless of tumor size and are potential predictors of RCC metastasis.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The receptor for hyaluronan (HA)-mediated motility (RHAMM) is a HA-binding protein located in the cytoskeleton and centrosome. RHAMM has multiple functions that manifest with different cellular localizations, for example, modulation of growth factor receptor, regulation of cell signaling pathways, and mitotic spindle assembly. In addition, its increased expression has major roles in tumorigenesis and can induce genomic instability and cancer progression. In head and neck cancers, increased expression of RHAMM is associated with high proliferation of cancer cells and decreased survival. CD44, a cell-adhesion molecule and HA receptor, can modulate intracellular signaling by forming complexes with RHAMM to promote invasion and metastasis of cancer cells. In this review, we provide an overview of the biological functions of RHAMM in non-neoplastic cells and cancer cells, as well as its association with CD44, and also introduce studies that particularly implicate RHAMM in the pathogenesis of head and neck cancers.
    Journal of Cancer Research and Clinical Oncology 03/2014; · 2.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular characterization of renal cell carcinoma may help differentiate benign oncocytoma from malignant renal cell carcinoma subtypes and predict metastasis. Chemokines, eg IL-8 and chemokine receptors such as CXCR4 and 7, promote inflammation and metastasis. SDF-1 is a CXCR4 and 7 ligand with 6 known isoforms. We evaluated the expression of these chemokines and chemokine receptors in kidney specimens. Using quantitative polymerase chain reaction we measured mRNA levels of IL-8, CXCR4 and 7, and SDF1 isoforms α, β and γ in a total of 166 specimens from 86 patients, including 86 tumor samples and 80 matched normal kidney samples. Mean ± SD followup was 18.9 ± 12 months (median 19.5). Renal cell carcinoma specimens included the clear cell, papillary and chromophobe subtype in 65, 10 and 5 cases, respectively, and oncocytoma in 6. A total of 17 cases were positive for metastasis. Median CXCR4 and 7, and SFD1-γ levels were increased twofold to tenfold. SDF1-α and β were unchanged or lower in clear cell renal cell carcinoma and papillary tumors than in normal tissue. Median SDF1-γ, IL-8, and CXCR4 and 7 were increased threefold to fortyfold in chromophobe tumors compared to oncocytoma. CXCR4 and 7 were increased in tumors less than 4 cm (mean 3,057 ± 2,230 and 806 ± 691) compared to oncocytoma (336 ± 325 and 201 ± 281, respectively, p ≤0.016). On multivariate analysis CXCR4 (p = 0.01), CXCR7 (p = 0.02) and SDF1-β (p = 0.005) were independently associated with metastasis. Combined CXCR7 plus SDF1-α and CXCR7 plus IL-8 markers showed the highest sensitivity (71% to 81%) and specificity (75% to 80%) of all individual or combined markers. Chemokines and chemokine receptors differentiate renal cell carcinoma and oncocytoma. Combined SDF1-α plus CXCR7 and IL-8 plus CXCR7 markers have about 80% accuracy for predicting renal cell carcinoma metastasis.
    The Journal of urology 03/2012; 187(3):827-33. · 3.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: Current treatments for metastatic RCC (mRCC) do not extend survival beyond a few months. Sorafenib (SF) is a targeted drug approved for mRCC, but it has modest efficacy. Hymecromone is a nontoxic dietary supplement with some antitumor activity at high doses (450 - 3000 mg/day). HC inhibits hyaluronic acid (HA) synthesis. HA promotes tumor growth and metastasis. We recently showed that HA-receptors CD44 and RHAMM are potential predictors of mRCC. We examined the anti-tumor properties of HC, SF, and their combination in RCC models. METHODS: Using proliferation, clonogenic and apoptosis assays, effects of HC (0-32 μg/ml), SF (0-3.2 μg/ml) and HC+SF were examined in RCC cells (Caki-1, 786-O, ACHN, A498) and endothelial cells (HMVEC-L, HUVEC). Boyden chamber was used for motility and invasion assays. Apoptosis indicators, HA receptors, EGFR and c-Met were evaluated by immunoblotting. Efficacy of HC, SF and HC+SF was evaluated in the SF-resistant Caki-1 xenograft model. RESULTS: HC+SF synergistically inhibited proliferation (>95%), motility/invasion (65%) and capillary formation (76%) in RCC and/or endothelial cells, and induced apoptosis by 8-fold (P<0.001). HC+SF inhibited HA synthesis and HA addition reversed the cytotoxicity of HC+SF. HC+SF up-regulated pro-apoptotic indicators and downregulated Mcl-1, CD44, RHAMM, phospho-EGFR and phospho-cMet levels. In all assays, HC and SF alone were ineffective. Oral administration of HC (50-200mg/kg) plus SF (30mg/kg) eradicated Caki-1 tumor growth without toxicity. HC and SF alone were ineffective. CONCLUSION: This is the first study that demonstrates combination of SF with HC a non-toxic dietary supplement is highly effective in controlling RCC.
    The Journal of urology 12/2012; · 3.75 Impact Factor


Available from
May 30, 2014