Nikhil C Munshi

Harvard Medical School, Boston, Massachusetts, United States

Are you Nikhil C Munshi?

Claim your profile

Publications (363)2758.78 Total impact

  • Jooeun Bae, Nikhil C. Munshi, Kenneth C. Anderson
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple myeloma (MM) is a B-cell malignancy characterized by the clonal proliferation of malignant plasma cells in the bone marrow and the development of osteolytic bone lesions. MM has emerged as a paradigm within the cancers for the success of drug discovery and translational medicine. This article discusses immunotherapy as an encouraging option for the goal of inducing effective and long-lasting therapeutic outcome. Divided into two distinct approaches, passive or active, immunotherapy, which targets tumor-associated antigens has shown promising results in multiple preclinical and clinical studies.
    Hematology/Oncology Clinics of North America. 10/2014; 28(5):927–943.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family that has been recently linked to tumor development. However, its role in modulating multiple myeloma (MM) biology and disease progression remains unexplored. We first demonstrated that patients with MM present with higher expression of Pyk2 compared to healthy individuals. By using loss-of-function approaches we defined that Pyk2 inhibition led to reduction of MM tumor growth in vivo as well as decreased cell proliferation, cell cycle progression and adhesion ability in vitro. In turn, overexpression of Pyk2 promoted the malignant phenotype, substantiated by enhanced tumor growth and reduced survival. Mechanistically, inhibition of Pyk2 reduced activation of Wnt/β-catenin signaling by destabilizing β-catenin, leading to down-regulation of c-Myc and Cyclin D1. Furthermore, treatment of MM cells with the FAK/Pyk2 inhibitor VS-4718, effectively inhibited MM cell growth both in vitro and in vivo. Collectively, our findings describe the tumor-promoting role of Pyk2 in MM, thus providing molecular evidence for a novel tyrosine kinase inhibitor as a new therapeutic option in MM.
    Blood 09/2014; · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Multiple myeloma patients who are refractory to lenalidomide and bortezomib have a dismal prognosis. Pomalidomide is a new immunomodulatory agent approved for the treatment of relapsed and refractory multiple myeloma (RRMM) that is unique in that it demonstrates promising activity but appears to be associated with lower toxicity than thalidomide or lenalidomide.Areas covered: We review the mechanisms of action of pomalidomide, evaluate preclinical data, summarize the results of dose-finding Phase I studies and describe Phase II/III studies of this drug in combination with dexamethasone and other agents. Data presented were gathered from multiple sources, including articles from PubMed, published abstracts from the annual meetings of the American Society of Hematology and American Society of Clinical Oncology and websites such as http://clinicaltrials.gov/.Expert opinion: The regulatory approval of pomalidomide represents an important addition to a hematologist’s armamentarium for the treatment of RRMM. Pomalidomide is well tolerated and demonstrates a high level of anti-myeloma activity. Pomalidomide combined with dexamethasone should be considered as standard-of-care therapy for advanced RRMM following progression on both lenalidomide and bortezomib. Ongoing and future studies will characterize the activity of different combinations intended to improve treatment responses, and the potential role of pomalidomide as maintenance therapy.
    Expert Opinion on Orphan Drugs. 09/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Waldenström's macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications (hyperviscosity, neuropathy). Mature studies show that rituximab combinations with cyclophosphamide/dexamethasone (DRC), or bendamustine (BR) or bortezomib/dexamethasone (BDR) provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second generation proteasome inhibitors (carfilzomib), mTOR inhibitors and BTK inhibitors, are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long lasting remission re-use of a prior effective regimen may be appropriate. AutoSCT may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.
    Blood 07/2014; · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Here we report that targeting casein kinase 1 (CSNK1α1) is a potential novel treatment strategy in multiple myeloma (MM) therapy distinct from proteasome inhibition. CSNK1α1 is expressed in all the tested MM cell lines and patient MM cells, and is not altered during bortezomib-triggered cytotoxicity. Inhibition of CSNK1α1 kinase activity in MM cells with targeted therapy D4476 or shRNAs triggers cell G0/G1 phase arrest, prolonged G2/M phase, and apoptosis. D4476 also induced cytotoxicity in bortezomib-resistant MM cells and enhances bortezomib-triggered cytotoxicity. CSNK1α1 signaling pathways include CDKN1B, P53 and FADD; gene signatures involved included interferon alpha (IFNα), tumor necrosis factor alpha (TNFα), and LIN9. Additionally, reduction of Csnk1α1 prevents cMYC/KRAS12V transformation of BaF3 cells independent of IL3. Impartially, reducing Csnk1α1 prevented development of cMYC/KRAS12V-induced plasmacytomas (PCTs) in mice, suggesting that CSNK1α1 may be involved in MM initiation and progression. Our data suggest that targeting CSNK1α1, alone or combined with bortezomib, is a potential novel therapeutic strategy in MM. Moreover, inhibition of CSNK1α1 may prevent the progression of monoclonal gammopathy of undetermined significance (MGUS) to MM.Leukemia accepted article preview online, 25 June 2014; doi:10.1038/leu.2014.202.
    Leukemia. 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND Multiple myeloma (MM) patients may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures due to long-term aminobisphosphonate (aBP) therapy. However, it is unknown whether NTX or other bone biomarkers are predictive of skeletal-related events (SRE) or the impact of cessation of aBP therapy on bone remodeling. METHODS We studied markers of bone turnover over a 6-month period after a single dose of zoledronic acid in 29 MM patients in remission who previously received 8-12 doses of pamidronate or zoledronate (NCT00577642). Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronate. A secondary objective was to identify and correlate other markers of bone remodeling with NTX changes. Thirty cytokines, based on their possible role in bone remodeling, were tested using cytokine arrays. Candidates were confirmed by ELISA. RESULTS All patients had continued suppression of NTX levels, except one patient who had an increase in NTX levels associated with an SRE. GDF-15 and decorin were found to decrease, while bone-specific alkaline phosphatase (BSALP) increased. Although not significant in aggregate, osteopontin and osteoprotegerin levels increased in at least half of the patients. CONCLUSION Our data show that NTX levels continue to be suppressed after aBP therapy and suggest that suppressed NTX levels may be predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP may be reversible in myeloma. This data provide the basis for less frequent dosing of aBPs.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: We evaluated a cocktail of HLA-A2-specific peptides including heteroclitic XBP1 US184-192 (YISPWILAV), heteroclitic XBP1 SP367-375 (YLFPQLISV), native CD138260-268 (GLVGLIFAV) and native CS1239-247 (SLFVLGLFL), for their ability to elicit multipeptide-specific cytotoxic T lymphocytes (MP-CTLs) using T cells from smoldering multiple myeloma (SMM) patients. Our results demonstrate that MP-CTLs generated from SMM patients' T cells show effective anti-MM responses including CD137 (4-1BB) upregulation, CTL proliferation, interferon-γ production and degranulation (CD107a) in an HLA-A2-restricted and peptide-specific manner. Phenotypically, we observed increased total CD3(+)CD8(+) T cells (>80%) and cellular activation (CD69(+)) within the memory SMM MP-CTL (CD45RO(+)/CD3(+)CD8(+)) subset after repeated multipeptide stimulation. Importantly, SMM patients could be categorized into distinct groups by their level of MP-CTL expansion and antitumor activity. In high responders, the effector memory (CCR7(-)CD45RO(+)/CD3(+)CD8(+)) T-cell subset was enriched, whereas the remaining responders' CTL contained a higher frequency of the terminal effector (CCR7(-)CD45RO(-)/CD3(+)CD8(+)) subset. These results suggest that this multipeptide cocktail has the potential to induce effective and durable memory MP-CTL in SMM patients. Therefore, our findings provide the rationale for clinical evaluation of a therapeutic vaccine to prevent or delay progression of SMM to active disease.Leukemia advance online publication, 17 June 2014;doi:10.1038/leu.2014.159.
    Leukemia. 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: With advent of several treatment options in multiple myeloma, a selection of effective regimen has become an important issue. Use of GEP is considered an important tool in predicting outcome; however, it is unclear whether such genomic analysis alone can adequately predict therapeutic response. We evaluated ability of GEP to predict complete response in MM. GEP from pre-treatment MM cells from 136 uniformly treated MM patients with response data on an IFM, France led study were analyzed. To evaluate variability in predictive power due to microarray platform or treatment types, additional datasets from three different studies (n=511) were analyzed using same methods. We used several machine learning methods to derive a prediction model using training and test subsets of the original four datasets. Among all methods employed for GEP-based CR predictive capability, we got accuracy range of 56% to 78% in test datasets and no significant difference with regard to GEP platforms, treatment regimens or in newly-diagnosed or relapsed patients. Importantly, permuted P-value showed no statistically significant CR predictive information in GEP data. This analysis suggests that GEP-based signature has limited power to predict CR in MM, highlighting the need to develop comprehensive predictive model using integrated genomics approach.Leukemia accepted article peview online, 15 April 2014. doi:10.1038/leu.2014.140.
    Leukemia 04/2014; · 10.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: With advent of several treatment options in multiple myeloma, a selection of effective regimen has become an important issue. Use of GEP is considered an important tool in predicting outcome; however, it is unclear whether such genomic analysis alone can adequately predict therapeutic response. We evaluated ability of GEP to predict complete response in MM. GEP from pre-treatment MM cells from 136 uniformly treated MM patients with response data on an IFM, France led study were analyzed. To evaluate variability in predictive power due to microarray platform or treatment types, additional datasets from three different studies (n=511) were analyzed using same methods. We used several machine learning methods to derive a prediction model using training and test subsets of the original four datasets. Among all methods employed for GEP-based CR predictive capability, we got accuracy range of 56% to 78% in test datasets and no significant difference with regard to GEP platforms, treatment regimens or in newly-diagnosed or relapsed patients. Importantly, permuted P-value showed no statistically significant CR predictive information in GEP data. This analysis suggests that GEP-based signature has limited power to predict CR in MM, highlighting the need to develop comprehensive predictive model using integrated genomics approach.Leukemia accepted article peview online, 15 April 2014. doi:10.1038/leu.2014.140.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2014; · 10.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5 0 truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.
    04/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE. The purpose of this study was to describe the MRI features of extramedullary myeloma and to evaluate the role of MRI in extramedullary myeloma. MATERIALS AND METHODS. The cases of 28 patients (15 men, 13 women; mean age, 57.53 years; range, 34-83 years) with extramedullary myeloma who underwent MRI at one institution from January 2004 through December 2012 were retrospectively identified through an electronic search of an institutional radiology database. Two radiologists reviewed images from 44 MRI examinations in consensus to document the morphologic, signal-intensity, and enhancement characteristics of extramedullary myeloma. Electronic medical records were reviewed to document the indication for MRI and subsequent management of extramedullary myeloma. RESULTS. A total of 72 sites of extramedullary myeloma were noted, most commonly the paraspinal-epidural location (28/72, 39%). Two radiologic patterns were identified: lesions contiguous with bone (n = 44) and lesions noncontiguous with bone (n = 28). Lesions contiguous with bone were larger (p = 0.001; Student t test). Of 28 paraspinal-epidural lesions, 13 compressed the cord. Compared with skeletal muscle, most of the lesions were hypointense to isointense on T1-weighted images (67/72, 93.1%) and isointense to hyperintense on T2-weighted images (62/72, 86.1%). Lesions noncontiguous with bone were more often hypointense on T2-weighted images (8/28 vs 2/44; p = 0.006; Fisher exact test). Neurologic symptoms prompted MRI in most cases (n = 32/44). MRI was helpful in management by radiotherapy and surgery (19/28). CONCLUSION. Extramedullary myeloma can be contiguous or noncontiguous with bone. Lesions contiguous with bone are larger, often occur in a paraspinal or epidural location, and can cause cord compression. Lesions noncontiguous with bone can be T2 hypointense. MRI helps in treatment planning.
    American Journal of Roentgenology 04/2014; 202(4):803-10. · 2.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has been studied in multiple myeloma (MM) but lacks significant single agent activity. Based on preclinical studies showing synergistic activity of mTOR inhibitors with lenalidomide, we studied the combination of lenalidomide and everolimus in relapsed or refractory MM in a phase I clinical trial. We assessed patient samples using gene expression, Western blotting and immunohistochemistry to probe the mTOR pathway. Twenty-six patients were evaluable for toxicity. Dose-limiting toxicities included grade 4 neutropenia and thrombocytopenia. The maximum tolerated dose was lenalidomide 15 mg and everolimus 5 mg for 21 d with a 7 d rest period. Grade 3/4 adverse events included thrombocytopenia (35%) and neutropenia (42%). The overall response rate was 65% (1 complete response + 4 partial response + 10 minimal response). The median progression-free survival was 5·5 months and median overall survival was 29·5 months. Biomarker data demonstrated downregulation of phosphorylated p70S6K. Gene expression profiling suggested activation of mTOR in responders versus non-responders. The combination of lenalidomide and everolimus was well tolerated with predictable toxicities and showed responses in a heavily pretreated population. When confirmed with larger patient numbers, this analysis may guide patient selection for future clinical trials of mTOR inhibition in MM.
    British Journal of Haematology 04/2014; · 4.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sp1 transcription factor controls a pleiotropic group of genes and its aberrant activation has been reported in number of malignancies including multiple myeloma. Here we investigated and report its aberrant activation in Waldenstrom's macroglobulinemia (WM). Both loss of - and gain of Sp1 function studies have highlighted a potential oncogenic role of Sp1 in WM. We have further investigated effect of a small molecule inhibitor (Terameprocol-TMP) targeting Sp1 activity in WM. Treatment with TMP inhibited growth and survival and impaired NF-κB and STAT3 activity in WM cells. We next investigated and observed that TMP treatment induced further inhibition of WM cells in MYD88 knock-down WM cells. Moreover, we observed that BTK, a downstream target of MYD88 signaling pathway, is transcriptionally regulated by Sp1 in WM cells. Combined use of TMP with BTK or IRAK1/4 inhibitors resulted in significant and synergistic dose-dependent antiproliferative effect in MYD88 L265P-expressing WM cells. In summary, these results demonstrate Sp1 as an important transcription factor that regulates proliferation and survival of WM cells independent of MYD88 pathway activation and provide preclinical rationale for clinical development of TMP in WM alone or in combination with inhibitors of MYD88 pathway.
    Blood 03/2014; · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, including the deadly plasma cell cancer multiple myeloma. In this study, we report that downregulation of the tumor suppressor microRNA miR-30-5p is a frequent pathogenetic event in multiple myeloma. Evidence was developed that miR-30-5p downregulation occurs as a result of interaction between multiple myeloma cells and bone marrow stromal cells, which in turn enhances expression of BCL9, a transcriptional coactivator of the Wnt signaling pathway known to promote multiple myeloma cell proliferation, survival, migration, drug resistance, and formation of multiple myeloma cancer stem cells. The potential for clinical translation of strategies to re-express miR-30-5p as a therapeutic approach was further encouraged by the capacity of miR-30c and miR-30 mix to reduce tumor burden and metastatic potential in vivo in three murine xenograft models of human multiple myeloma without adversely affecting associated bone disease. Together, our findings offer a preclinical rationale to explore miR-30-5p delivery as an effective therapeutic strategy to eradicate multiple myeloma cells in vivo. Cancer Res; 74(6); 1-13. ©2014 AACR.
    Cancer Research 03/2014; · 9.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: B cell maturation antigen (BCMA), highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies. We here show that BCMA is universally expressed on the MM cell surface and determine specific anti-MM activity of J6M0-mcMMAF (GSK2857916), a novel humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker. J6M0-mcMMAF specifically blocks cell growth via G2/M arrest and induces caspase 3-dependent apoptosis in MM cells, alone and in coculture with bone marrow stromal cells (BMSC) or various effector cells. It strongly inhibits colony formation by MM cells while sparing surrounding BCMA-negative normal cells. J6M0-mcMMAF significantly induces effector cell-mediated lysis against allogeneic or autologous patient MM cells, with increased potency and efficacy compared to the wild-type J6M0 without Fc enhancement. The ADCC and apoptotic activity of J6M0-mcMMAF is further enhanced by lenalidomide. Importantly, J6M0-mcMMAF rapidly eliminates myeloma cells in subcutaneous and disseminated mouse models, and mice remain tumor-free up to 3.5 months. Furthermore, J6M0-mcMMAF recruits macrophages and mediates antibody-dependent cellular phagocytosis (ADCP) of MM cells. Together, these results demonstrate that GSK2857916 has potent and selective anti-MM activities via multiple cytotoxic mechanisms, providing a promising next-generation immunotherapeutic in this cancer.
    Blood 02/2014; · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment.
    Nature Communications 01/2014; 5:2997. · 10.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this prospective, multicenter, phase 2 study, 64 patients with relapsed or relapsed and refractory multiple myeloma (MM) received up to eight 21-day cycles of bortezomib 1.0 mg/m(2) (days 1, 4, 8, 11), lenalidomide 15 mg/day (days 1-14), and dexamethasone 40/20 mg/day (cycles 1-4) and 20/10 mg/day (cycles 5-8) (days of/after bortezomib dosing). Responding patients could receive maintenance therapy. Median age was 65 years, 66% were male, 58% had relapsed and 42% relapsed and refractory MM, and 53%, 75%, and 6% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Forty eight of 64 patients (75%; 90% CI, 65-84) were alive without progressive disease at 6 months (primary endpoint). The rate of partial response or better was 64%; median duration of response was 8.7 months. Median progression-free and overall survival were 9.5 and 30 months, respectively (median follow-up: 44 months). Common treatment-related toxicities included sensory neuropathy (53%), fatigue (50%), and neutropenia (42%); common grade 3/4 treatment-related toxicities included neutropenia (30%), thrombocytopenia (22%), and lymphopenia (11%). Grade 3 motor neuropathy was reported in two patients. Lenalidomide-bortezomib-dexamethasone appears effective and tolerable in patients with relapsed or relapsed and refractory MM, demonstrating substantial activity among patients with diverse prior therapies and adverse prognostic characteristics. This trial is registered with www.ClinicalTrials.gov as #NCT00378209.
    Blood 01/2014; · 9.78 Impact Factor
  • Nikhil C Munshi, Kenneth C Anderson
    Journal of Clinical Oncology 01/2014; · 18.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.
    Nature Communications 01/2014; 5:3644. · 10.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been associated with colorectal cancer growth and metastasis, however, a causal role for CCL20 signaling through CCR6 in promoting intestinal carcinogenesis has not been demonstrated in vivo. In this study, we aimed to determine the role of CCL20-CCR6 interactions in spontaneous intestinal tumorigenesis. CCR6-deficient mice were crossed with mice heterozygous for a mutation in the adenomatous polyposis coli (APC) gene (APCMIN/+ mice) to generate APCMIN/+ mice with CCR6 knocked out (CCR6KO-APCMIN/+ mice). CCR6KO-APCMIN/+ mice had diminished spontaneous intestinal tumorigenesis. CCR6KO-APCMIN/+ also had normal sized spleens as compared to the enlarged spleens found in APCMIN/+ mice. Decreased macrophage infiltration into intestinal adenomas and non-tumor epithelium was observed in CCR6KO-APCMIN/+ as compared to APCMIN/+ mice. CCL20 signaling through CCR6 caused increased production of CCL20 by colorectal cancer cell lines. Furthermore, CCL20 had a direct mitogenic effect on colorectal cancer cells. Thus, interactions between CCL20 and CCR6 promote intestinal carcinogenesis. Our results suggest that the intestinal tumorigenesis driven by CCL20-CCR6 interactions may be driven by macrophage recruitment into the intestine as well as proliferation of neoplastic epithelial cells. This interaction could be targeted for the treatment or prevention of malignancy.
    PLoS ONE 01/2014; 9(5):e97566. · 3.73 Impact Factor

Publication Stats

17k Citations
2,758.78 Total Impact Points

Institutions

  • 2002–2014
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
    • Dana-Farber Cancer Institute
      • • Department of Medical Oncology
      • • Bing Center for Waldenstrom's Macroglobulinemia
      Boston, Massachusetts, United States
  • 2013
    • Tongji University
      Shanghai, Shanghai Shi, China
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 2012
    • Thomas Jefferson University
      • Division of Internal Medicine
      Philadelphia, PA, United States
  • 2004–2012
    • University of Leeds
      • School of Medicine
      Leeds, England, United Kingdom
  • 2011
    • Athens State University
      Athens, Alabama, United States
    • Novartis Institutes for BioMedical Research
      Cambridge, Massachusetts, United States
  • 2008–2010
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
    • Universita' degli Studi "Magna Græcia" di Catanzaro
      Catanzaro, Calabria, Italy
  • 2009
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
    • National Institutes of Health
      Maryland, United States
  • 2005–2008
    • Harvard University
      • Department of Stem Cell and Regenerative Biology
      Cambridge, Massachusetts, United States
  • 2007
    • Hospital of the University of Pennsylvania
      • Division of Hematology/Oncology
      Philadelphia, Pennsylvania, United States
  • 2006
    • Mayo Foundation for Medical Education and Research
      • Division of Hematology
      Scottsdale, AZ, United States
  • 1996–2005
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
  • 2003
    • Mayo Clinic - Rochester
      Rochester, Minnesota, United States
  • 1997–2002
    • University of Arkansas for Medical Sciences
      • Department of Internal Medicine
      Little Rock, Arkansas, United States
  • 2001
    • Central Arkansas Veterans Healthcare System
      Washington, Washington, D.C., United States
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 1999
    • University of South Carolina
      Columbia, South Carolina, United States