Pheroze Tamboli

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

Are you Pheroze Tamboli?

Claim your profile

Publications (155)693.15 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Angiogenesis plays a role in tumor growth and is partly mediated by factors in both the fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) pathways. Durable clinical responses with VEGF tyrosine kinase inhibitors (TKIs) may be limited by intrinsic tumor resistance. We hypothesized that FGF signaling may impact clinical responses to sorafenib. Nephrectomy material was available from 40 patients with metastatic renal cell carcinoma (RCC) enrolled in a phase II clinical trial of sorafenib ± interferon (ClinicalTrials.gov Identifier NCT00126594). Fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor receptor substrate 2 alpha (FRS2α) expression was assessed by in situ hybridization and immunofluorescence, respectively. The relationship between fibroblast growth factor pathway marker levels and progression-free survival (PFS) was analyzed using Kaplan-Meier and Cox proportional hazards regression methods. Univariate analysis indicated that more intense FGFR1 staining was associated with shorter PFS (log-rank P = 0.0452), but FRS2α staining was not significantly associated with PFS (log-rank P = 0.2610). Multivariate Cox proportional hazards regression models were constructed for FGFR1 and FRS2α individually, adjusting for baseline Eastern Cooperative Oncology Group performance status, treatment arm and anemia status. When adjusted for each of these variables, the highest intensity level of FGFR1 (level 3 or 4) had increased progression risk relative to the lowest intensity level of FGFR1 (level 1) (P = 0.0115). The highest intensity level of FRS2α (level 3 or 4) had increased progression risk relative to the lowest intensity level of FRS2α (level 1) (P = 0.0126). Increased expression of FGFR1 and FRS2α was associated with decreased PFS among patients with metastatic RCC treated with sorafenib. The results suggest that FGF pathway activation may impact intrinsic resistance to VEGF receptor inhibition.
    BMC Cancer 04/2015; 15:304. DOI:10.1186/s12885-015-1302-1 · 3.32 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Isolated local retroperitoneal recurrence (RPR) after radical nephrectomy (RN) for renal cell carcinoma (RCC) poses a therapeutic challenge. We investigated the outcomes of patients with localized RPR treated with surgical resection. This was a retrospective single-institutional study of 102 patients with RPR treated with surgery from 1990-2014. Demographics, clinical and pathological features, location of RPR, perioperative complications were reported using descriptive statistics. Recurrence free survival (RFS) and cancer-specific survival (CSS) were studied using univariate and multivariate analyses. Median age at RPR diagnosis was 55 years (IQR 49-64). Sixty-two (60.8%) patients were pT3-4 and 20 (19.6%) were pN1. No patients had distant metastatic disease at time of RPR surgery. Median time from nephrectomy to RPR diagnosis was 19 months (IQR 5-38.8). The median size of resected RPR was 4.5cm (IQR 2.7-7). Median follow up after RPR surgery was 32 months (IQR 16-57). Metastatic progression was observed in 60 (58.8%) patients after RPR surgery. Neoadjuvant and salvage systemic therapy were administered in 46 (45.1%) and 48 (47.1%) patients, respectively. On multivariate analysis, pathological nodal stage at original nephrectomy and maximum diameter of RPR were identified as independent risk factors for cancer specific death. Clinico-pathological factors at the time of nephrectomy as well as RPR surgery are important prognosticators. Aggressive surgical resection offers potential cure in a substantial number of patients with RPR with acceptable complications, and still plays a dominant role in the management of isolated locally recurrent RCC. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is an aggressive malignancy associated with a poor prognosis. Although existing literature focuses on patients presenting with metastatic disease, characteristics and outcomes for patients with localized disease are not well described. We aimed to evaluate postnephrectomy characteristics, outcomes, and predictors of survival in patients with sRCC who presented with clinically localized disease. An institutional review board-approved review from 1986 to 2011 identified 77 patients who presented with clinically localized disease, underwent nephrectomy, and had sRCC in their primary kidney tumor. Clinical and pathologic variables were captured for each patient. Overall survival (OS) and recurrence-free survival (RFS) were calculated for all patients and those who had no evidence of disease (NED) following nephrectomy, respectively. Comparisons were made with categorical groupings in proportional hazards regression models for univariable and multivariable analyses. OS for the entire cohort (n = 77) at 2 years was 50%. A total of 56 (77%) patients of the 73 who has NED following nephrectomy experienced a recurrence, with a median time to recurrence of 26.2 months. On multivariable analysis, tumor stage, pathologically positive lymph nodes, and year of nephrectomy were significant predictors of both OS and recurrence-free survival. Limitations include the retrospective nature of this study and relatively small sample size. Long-term survival for patients with sRCC, even in clinically localized disease, is poor. Aggressive surveillance of those who have NED following nephrectomy is essential, and further prospective studies evaluating the benefit of adjuvant systemic therapies in this cohort are warranted. Copyright © 2014 Elsevier Inc. All rights reserved.
    Urologic Oncology 02/2015; DOI:10.1016/j.urolonc.2014.11.021 · 3.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and anti-angiogenic therapy is the current mainstay of treatment. RCC patients develop innate or adaptive resistance to anti-angiogenic therapy. There is a need to identify biomarkers which predict therapeutic resistance and guide combination therapy. Methods: Tissue microarrays with triplicate cores for each case were generated from 33 unaffected kidneys, 41 untreated primary RCC, and 42 bevacizumab and 39 sunitinib pretreated primary RCC from patients with metastatic RCC. Immunohistochemistry was used to visualize immune cell infiltration. Staining quantitation was performed using a Vectra multispectral system. Statistical analysis was performed using unpaired Student´s t-test. Results: We assessed the interaction between anti-angiogenic therapy and tumor immune microenvironment, and determined their impact on clinical outcome. Here we found that anti-angiogenic therapy treated RCC primary tumors demonstrated increased infiltration of CD4+ and CD8+ T lymphocytes, which was inversely related to patient survival. Furthermore, anti-angiogenic therapy treated specimens showed higher infiltration of CD4+FOXP3+regulatory T cells (Tregs) and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T lymphocyte infiltration and were negatively related to patient overall survival (OS) and/or progression free survival (PFS). Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Conclusions: This study indicates that anti-angiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy, and will guide the development of combination therapy with PD-1/PD-L1 blocking agents.
    2015 Genitourinary Cancers Symposium of the American Society of Clinical Oncology, J Clin Oncol 33, 2015 (suppl 7; abstr 419); 02/2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ror2 is a Wnt ligand receptor that is overexpressed in a variety of tumors including clear cell renal cell carcinoma (ccRCC). Here we demonstrate that expression of wild type Ror2 results in increased tumorigenic properties in in vitro cell culture and in vivo xenograft models. In addition, Ror2 expression produced positive changes in both cell migration and invasion, which were dependent on matrix metalloprotease 2 (MMP2) activity. Mutations in key regions of the kinase domain of Ror2 resulted in the abrogation of increased tumor growth, cell migration, and cell invasion observed with expression of wild-type Ror2. Finally, we examined Ror2 expression as a prognostic biomarker for ccRCC utilizing the TCGA ccRCC dataset. High expression of Ror2 showed a significant correlation with higher clinical stage, nuclear grade, and tumor stage. Furthermore, high expression of Ror2 in ccRCC patients correlated with significant lower overall survival, cancer specific survival, and recurrence free survival. Together, these findings suggest that Ror2 plays a central role in influencing the ccRCC phenotype, and can be considered as a negative prognostic biomarker and potential therapeutic target in this cancer.
    PLoS ONE 12/2014; 9(12):e116101. DOI:10.1371/journal.pone.0116101 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The etiologic heterogeneity of cancer has traditionally been investigated by comparing risk factor frequencies within candidate sub-types, defined for example by histology or by distinct tumor markers of interest. Increasingly tumors are being profiled for molecular features much more extensively. This greatly expands the opportunities for defining distinct sub-types. In this article we describe an exploratory analysis of the etiologic heterogeneity of clear cell kidney cancer. Data are available on the primary known risk factors for kidney cancer, while the tumors are characterized on a genome-wide basis using expression, methylation, copy number and mutational profiles. We use a novel clustering strategy to identify sub-types. This is accomplished independently for the expression, methylation and copy number profiles. The goals are to identify tumor sub-types that are etiologically distinct, to identify the risk factors that define specific sub-types, and to endeavor to characterize the key genes that appear to represent the principal features of the distinct sub-types. The analysis reveals strong evidence that gender represents an important factor that distinguishes disease sub-types. The sub-types defined using expression data and methylation data demonstrate considerable congruence and are also clearly correlated with mutations in important cancer genes. These sub-types are also strongly correlated with survival. The complexity of the data presents many analytical challenges including, prominently, the risk of false discovery. Genomic profiling of tumors offers the opportunity to identify etiologically distinct sub-types, paving the way for a more refined understanding of cancer etiology.
    BMC Medical Research Methodology 12/2014; 14(1):138. DOI:10.1186/1471-2288-14-138 · 2.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: During the last 30years many advances have been made in kidney tumor pathology. In 1981, 9 entities were recognized in the WHO Classification. In the latest classification of 2004, 50 different types have been recognized. Additional tumor entities have been described since and a wide variety of prognostic parameters have been investigated with variable success; however, much attention has centered upon the importance of features relating to both stage and grade. The International Society of Urological Pathology (ISUP) recommends after consensus conferences the development of reporting guidelines, which have been adopted worldwide ISUP undertook to review all aspects of the pathology of adult renal malignancy through an international consensus conference to be held in 2012. As in the past, participation in this consensus conference was restricted to acknowledged experts in the field. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
    Annales de Pathologie 12/2014; 34(6):448-61. DOI:10.1016/j.annpat.2014.10.003 · 0.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Intra-abdominal desmoplastic small round cell tumor (DSRCT) is a rare, aggressive tumor affecting adolescent and young males. DSRCT presenting as a primary renal mass in the absence of visceral or serosal involvement is extremely rare. Herein, we present the pathologic and molecular findings in the case of a young man who presented with a large renal mass without any visceral or serosal involvement. Noticeably, the tumor lacked prominent desmoplastic stroma and only focally expressed cytokeratin, both of which are considered characteristic histologic features for this tumor. Fluorescence in situ hybridization studies using an EWSR1 break-apart probe confirmed the presence of a rearrangement involving the EWSR1 locus and RT-PCR demonstrated the presence of an EWSR1-WT1 fusion transcript associated with the t(11;22) rearrangement, which supported a diagnosis of DSRCT. We also discuss the differential diagnostic considerations faced by the pathologist in the workup of small round cell neoplasms of the kidney.
    Pathology - Research and Practice 12/2014; 210(12). DOI:10.1016/j.prp.2014.05.013 · 1.56 Impact Factor
  • Priya Rao, Pheroze Tamboli
    Human pathology 11/2014; 46(2). DOI:10.1016/j.humpath.2014.10.023 · 2.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective To characterize the clinical, radiologic and histologic features of Mucinous Tubular and Spindle Cell Carcinoma (MTSCC), as well as oncologic outcomes.Patients and methodsThis is a single institution retrospective analysis of all MTSCC patients from 2002-2011.Patients were excluded if MTSCC could not be confirmed on pathology re-review (n=4).Clinical characteristics, pathology, imaging, and outcomes were reviewed for the 19 included patients.ResultsMedian age at diagnosis was 59 years (range 17-71) with a female predominance (78.9%).On contrast enhanced CT scan, MTSCC enhanced less than the cortex during the corticomedullary phase. Mean tumor attenuation was 36 HU (range 24-48), 67 HU (range 41-133), 89 HU (range 49-152), and 76 HU (range 52-106) in the precontrast, corticomedullary, nephrographic and excretory phases, respectively.Sixteen patients were treated with partial (N=5) or radical nephrectomy (N=11) for pT1(62.5%), pT2(31.3%), and pT3a disease(6.3%). One patient had active surveillance. Of 3 patients(13.0%) managed with energy ablation, there was one recurrence that was treated with salvage surgery.One patient(5.3%) had metastatic disease at diagnosis and died of disease 64.7 months later. A patient with a pT2bN0M0 MTSCC with sarcomatoid dedifferentiation developed bone metastases 9.5 months after diagnosis and was alive at 19.0 months. The remainder were free of recurrence or progression.ConclusionMTSCC is a rare RCC variant. In this largest series to date, MTSCC presented at a broad range of ages and displayed a female predilection.Imaging and pathologic features of MTSCC display some overlap with papillary RCC.MTSCC is associated with excellent outcomes overall, but is not universally indolent.
    BJU International 11/2014; DOI:10.1111/bju.12992 · 3.13 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients with locally advanced renal cell carcinoma (RCC) represent a subset of patients who may benefit from retroperitoneal lymph node dissection (RPLND). We aimed to identify preoperative clinical predictors of positive lymph nodes in patients with RCC without distant metastasis who underwent RPLND.
    The Journal of Urology 10/2014; DOI:10.1016/j.juro.2014.10.096 · 3.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Clear cell papillary renal cell carcinoma (CCPRCC) is a renal neoplasm that has recently received widespread recognition in the literature. There have been several reports of this tumor arising in a sporadic setting and in patients with end-stage renal disease; however, there is limited information available about the clinical, pathologic, and genetic characteristics of this tumor in the setting of Von Hippel-Lindau (VHL) disease. We herein report a series of three patients that developed CCPRCC in this unique clinical setting. The histology and immunohistochemical profile for all three cases was similar to that which has been previously reported for CCPRCC. All tumors were diffusely and strongly positive for Cytokeratin 7, negative for alpha methyl Co-A racemase and showed at least focal staining for CD10. Comparative genomic analysis was performed on tumors from all three patients. One tumor demonstrated monosomy 3 and the other two tumors showed normal chromosomal content. All three patients were alive without evidence of disease progression 5, 3 and 3 years after surgery. CCPRCC represents a distinct tumor type that may occur in the setting of VHL disease and should be considered in the differential diagnosis of extensively cystic renal tumors arising in this clinical setting. Molecular analysis in our series of cases suggests that CCPRCC does indeed represent a unique histologic subtype and must be distinguished from clear cell renal cell carcinoma (CCRCC) due to different biologic potentials. Ancillary studies for accurate classification are recommended due to significant morphologic overlap with CCRCC.
    Human pathology 09/2014; 45(9). DOI:10.1016/j.humpath.2014.06.004 · 2.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Published experience remains limited for glandular neoplasms of the urachus, especially mucinous cystic tumors. We reviewed 55 glandular urachal neoplasms to evaluate their clinical features and histopathologic spectrum and to devise a classification system for the mucinous cystic forms. Within the 55 cases studied, we observed 2 groups with differing clinical, gross, and histopathologic features. The first group, invasive, noncystic adenocarcinomas (n=24), had clinicopathologic features in accord with the known spectrum of urachal adenocarcinoma (mean age 50 y, female:male ratio 1.7, with recurrence or death from disease in 9/16 cases over a 45 mo mean follow-up). The second group, mucinous cystic tumors (n=31), morphologically resembled mucinous cystic tumors of the ovary and appeared classifiable by the same approach (mean age 47 y, female:male ratio 1.4) and included mucinous cystadenoma (n=4), mucinous cystic tumor of low malignant potential (n=22, including 2 cases with intraepithelial carcinoma), and mucinous cystadenocarcinoma with microscopic (n=4) or frank invasion (n=1). Follow-up information was available for 13 patients with mucinous cystic tumors (mean 41 mo); we observed no local recurrence or distant metastasis. This experience suggests that there is a distinct group of glandular, cystic tumors of the urachus that is classifiable in a manner similar to ovarian neoplasms and that has a favorable prognosis after complete excision. As with cystic neoplasms of other organs, rigorous sampling is recommended to identify potentially small foci of carcinoma that could be missed by inadequate sampling. Accordingly, classification based on methods other than complete surgical excision may be hazardous.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Cytoreductive nephrectomy (CN) remains the standard of care for appropriately selected patients with metastatic renal cell carcinoma (mRCC). Although the role of partial nephrectomy (PN) is well accepted in patients with localized disease, limited data are available regarding PN in the metastatic setting. We sought to identify the indications and outcomes for PN in the setting of mRCC with particular attention to different PN subgroups. Materials and Methods: We analyzed data from a consecutive cohort of 33 patients with mRCC who underwent PN at a single institution between 1996 and 2011. Non-parametric statistics were used to compare PN subgroups. Overall survival (OS) was estimated using Kaplan-Meier method, and survival functions were compared using the log-rank test. Results: Eight patients presented with bilateral synchronous renal masses; 20 with a metachronous contralateral renal mass; and 5 with a unilateral renal mass. Overall, 22 patients (67%) died of disease at a median of 27 months after PN. Patients who underwent PN for a metachronous contralateral renal mass and for a renal mass ≤4cm had the best OS (61 months and 42 months, respectively). Median OS for patients with and without metastatic disease at original diagnosis was 27 and 63 months, respectively (p=0.003). Conclusions: Our findings suggest that the presence of metastasis at original diagnosis and the timing of presentation of the PN index lesion play an important role in survival. These factors should be taken into consideration when determining which patients would benefit from partial nephrectomy in the setting of mRCC.
    The Journal of urology 07/2014; 192(1). DOI:10.1016/j.juro.2014.01.086 · 3.75 Impact Factor
  • The Journal of Urology 04/2014; 191(4):e386-e387. DOI:10.1016/j.juro.2014.02.1084 · 3.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Previous studies have shown a modest impact of tyrosine kinase inhibitors on primary renal tumors. Those studies were mostly retrospective and heterogeneous in their eligibility criteria with regard to histology, disease stage, duration of therapy, and time off therapy prior to surgery. Objective To prospectively investigate the safety and efficacy of axitinib in downsizing tumors in patients with nonmetastatic biopsy-proven clear cell renal cell carcinoma (ccRCC). Design, setting, and participants This was a single-institution, single-arm phase 2 clinical trial. Patients with locally advanced nonmetastatic biopsy-proven ccRCC were eligible. Intervention Patients received axitinib 5 mg for up to 12 wk. Axitinib was continued until 36 h prior to surgery. Patient underwent partial or radical nephrectomy after axitinib therapy. Outcome measurements and statistical analysis The primary outcome was objective response rate prior to surgery. Secondary outcomes included safety, tolerability, and quality of life. A dedicated radiologist independently reviewed all computed tomography scans to evaluate for response using Response Evaluation Criteria in Solid Tumors (RECIST). Results and limitations A total of 24 patients were treated. Twenty-two patients continued axitinib for 12 wk; 1 patient continued axitinib for 11 wk and underwent surgery as planned. One patient stopped treatment at 7 wk due to adverse events (AEs). Median reduction of primary renal tumor diameter was 28.3%. Eleven patients experienced a partial response per RECIST; 13 had stable disease. There was no progression of disease while on axitinib. The most common AEs were hypertension, fatigue, oral mucositis, hypothyroidism, and hand-foot syndrome. Postoperatively, 2 grade 3 and 13 grade 2 complications were noted. No grade 4 or 5 complications occurred. Functional Assessment of Cancer Therapy-Kidney Specific Index-15 changed over time, with quality of life worsening while on therapy, but by week 19, it was not statistically different from screening. Limitations include single-arm design and small patient numbers. Conclusions Axitinib was clinically active and reasonably well tolerated in the neoadjuvant setting in patients with locally advanced nonmetastatic ccRCC. Patient summary In this prospective clinical trial, we found that axitinib, when given prior to surgery, results in significant shrinking of kidney cancers. Larger studies are needed prior to further clinical use. Trial registration This clinical trial was registered with clinicaltrials.gov (NCT01263769).
    European Urology 04/2014; 66(5). DOI:10.1016/j.eururo.2014.01.035 · 12.48 Impact Factor
  • The Journal of Urology 04/2014; 191(4):e246. DOI:10.1016/j.juro.2014.02.877 · 3.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We report the case of a 67-year-old female who presented with a large renal mass. Gross examination of the nephrectomy specimen demonstrated a 6-cm renal mass that was invasive into the renal sinus and perinephric fat. Histologic examination revealed two distinct tumor types. The first type had a conventional (clear cell) renal cell carcinoma component that was of low nuclear grade and comprised the minority of the overall tumor. The second type had a high-grade collecting duct carcinoma component with glandular/tubular differentiation and was composed of the majority of the tumor. Immunohistochemical studies demonstrated distinctive patterns of the two tumor types, thus confirming two distinct lineages. Five months postoperatively, the patient developed metastasis to the lungs and right hilar lymph node region. A fine needle aspiration of a lung nodule demonstrated a metastatic, poorly differentiated carcinoma, similar to the collecting duct carcinoma component in the kidney. Collision tumors of the kidney are rare with fewer than ten cases reported in the literature. Our report further expands the spectrum of this rare phenomenon.
    Ai zheng = Aizheng = Chinese journal of cancer 03/2014; 33(7). DOI:10.5732/cjc.013.10155
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gene expression signatures have proven to be useful tools in many cancers to identify distinct subtypes of disease based on molecular features that drive pathogenesis, and to aid in predicting clinical outcomes. However, there are no current signatures for kidney cancer that are applicable in a clinical setting. To generate a signature biomarker for the clear cell renal cell carcinoma (ccRCC) good risk (ccA) and poor risk (ccB) subtype classification that could be readily applied to clinical samples to develop an integrated model for biologically defined risk stratification. A set of 72 ccRCC sample standards was used to develop a 34-gene classifier (ClearCode34) for assigning ccRCC tumors to subtypes. The classifier was applied to RNA-sequencing data from 380 nonmetastatic ccRCC samples from the Cancer Genome Atlas (TCGA), and to 157 formalin-fixed clinical samples collected at the University of North Carolina. Kaplan-Meier analyses were performed on the individual cohorts to calculate recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Training and test sets were randomly selected from the combined cohorts to assemble a risk prediction model for disease recurrence. The subtypes were significantly associated with RFS (p<0.01), CSS (p<0.01), and OS (p<0.01). Hazard ratios for subtype classification were similar to those of stage and grade in association with recurrence risk, and remained significant in multivariate analyses. An integrated molecular/clinical model for RFS to assign patients to risk groups was able to accurately predict CSS above established, clinical risk-prediction algorithms. The ClearCode34-based model provides prognostic stratification that improves upon established algorithms to assess risk for recurrence and death for nonmetastatic ccRCC patients. We developed a 34-gene subtype predictor to classify clear cell renal cell carcinoma tumors according to ccA or ccB subtypes and built a subtype-inclusive model to analyze patient survival outcomes.
    European Urology 02/2014; 66(1). DOI:10.1016/j.eururo.2014.02.035 · 12.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone is one of the common sites of metastases from renal cell carcinoma (RCC), however the mechanism by which RCC preferentially metastasize to bone is poorly understood. Homing/retention of RCC cells to bone and subsequent proliferation are necessary steps for RCC cells to colonize bone. To explore possible mechanisms by which these processes occur, we used an in vivo metastasis model in which 786-O RCC cells were injected into SCID mice intracardially, and organotropic cell lines from bone, liver, and lymph node were selected. The expression of molecules affecting cell adhesion, angiogenesis, and osteolysis were then examined in these selected cells. Cadherin-11, a mesenchymal cadherin mainly expressed in osteoblasts, was significantly increased on the cell surface in bone metastasis-derived 786-O cells (Bo-786-O) compared to parental, liver, or lymph node-derived cells. In contrast, the homing receptor CXCR4 was equivalently expressed in cells derived from all organs. No significant difference was observed in the expression of angiogenic factors, including HIF-1α, VEGF, angiopoeitin-1, Tie2, c-MET, and osteolytic factors, including PTHrP, IL-6 and RANKL. While the parental and Bo-786-O cells have similar proliferation rates, Bo-786-O cells showed an increase in migration compared to the parental 786-O cells. Knockdown of Cadherin-11 using shRNA reduced the rate of migration in Bo-786-O cells, suggesting that Cadherin-11 contributes to the increased migration observed in bone-derived cells. Immunohistochemical analysis of cadherin-11 expression in a human renal carcinoma tissue array showed that the number of human specimens with positive cadherin-11 activity was significantly higher in tumors that metastasized to bone than that in primary tumors. Together, these results suggest that Cadherin-11 may play a role in RCC bone metastasis.
    PLoS ONE 02/2014; 9(2):e89880. DOI:10.1371/journal.pone.0089880 · 3.53 Impact Factor

Publication Stats

4k Citations
693.15 Total Impact Points

Institutions

  • 2000–2015
    • University of Texas MD Anderson Cancer Center
      • • Department of Pathology
      • • Department of Urology
      Houston, Texas, United States
  • 2014
    • University of Otago
      Taieri, Otago, New Zealand
  • 2013
    • University of Texas Health Science Center at Houston
      Houston, Texas, United States
  • 2008
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Angeles, CA, United States
  • 2005–2007
    • University of Houston
      Houston, Texas, United States
  • 1999–2005
    • Emory University
      • Department of Pathology and Laboratory Medicine
      Atlanta, Georgia, United States
  • 2002
    • University of Wales
      Cardiff, Wales, United Kingdom
  • 1999–2002
    • Henry Ford Hospital
      • Surgery
      Detroit, Michigan, United States