Lloyd M Hutchinson

Harvard University, Cambridge, Massachusetts, United States

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Publications (7)30.52 Total impact

  • Jacqueline Banyard, Lloyd M Hutchinson, Bruce R Zetter
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    ABSTRACT: Thymosin beta15 is a small actin-binding protein upregulated in highly metastatic rat prostate cancer cells, relative to low metastatic cells. We have previously established an important role for thymosin beta15 as a diagnostic marker in human prostate cancer, with potential as a prognostic indicator. We here review the data supporting increased thymosin beta15 expression in other cancer types, including breast, brain, and lung. Human NB thymosin beta is a beta-thymosin originally found in neuroblastoma. New data demonstrate that NB thymosin beta represents the human homolog of rat thymosin beta15; thus we suggest classification as human thymosin beta15. In addition to the previously described gene, thymosin beta15a, we report the discovery of a new isoform of human thymosin beta15, thymosin beta15b, which is transcribed from an independent gene on human chromosome X. The gene structure of thymosin beta15a and beta15b is conserved and the isoforms show 87% identity across the nucleotide sequence. Across the coding sequence the nucleotide differences are silent, resulting in identical proteins. Other thymosin family members have recently been shown to exert potent clinical effects. The functional data available for thymosin beta15, combined with the tumor expression pattern, suggest that thymosin beta15 may play an important role in tumor development and progression in addition to its value as a biomarker in prostate cancer.
    Annals of the New York Academy of Sciences 10/2007; 1112:286-96. DOI:10.1196/annals.1415.024 · 4.31 Impact Factor
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    ABSTRACT: We had previously identified a new transmembrane collagen, type XXIII, in metastatic rat prostate carcinoma cells. The purpose of this study was to determine the expression of collagen XXIII in human prostate cancer and investigate its relationship with disease progression. We investigated collagen XXIII expression in prostate cancer tissue and did a retrospective analysis of association with prostate-specific antigen (PSA)-defined disease recurrence. The presence of collagen XXIII in prostate cancer patient urine was also assessed before and after prostatectomy. Collagen XXIII protein was detected at very low levels in benign prostate tissue and was significantly increased in prostate cancer. Distant metastases exhibited significantly higher collagen XXIII levels compared with either localized prostate cancer or regional (lymph node) metastases. Patients with high collagen XXIII levels had a 2.8-fold higher risk of PSA failure with median time to failure of 8.1 months, compared with low collagen XXIII patients with a median time to failure of 5 years. Multivariate Cox regression showed that the presence of collagen XXIII was significantly associated with time to PSA recurrence, independent of other clinical variables. Collagen XXIII was also detected in prostate cancer patient urine, with reduced levels after prostatectomy, indicating potential as a noninvasive fluid biomarker. We present the first report demonstrating increased collagen XXIII expression in prostate cancer tissue. We show that collagen XXIII level is a significant independent predictor of PSA-defined disease recurrence, suggesting a potential role as a molecular biomarker of prostate cancer progression and metastasis.
    Clinical Cancer Research 06/2007; 13(9):2634-42. DOI:10.1158/1078-0432.CCR-06-2163 · 8.19 Impact Factor
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    ABSTRACT: The disease state of cancer appears late in tumor development. Before being diagnosed, a tumor can remain for prolonged periods of time in a dormant state. Dormant human cancer is commonly defined as a microscopic tumor that does not expand in size and remains asymptomatic. Dormant tumors represent an early stage in tumor development and may therefore be a potential target for nontoxic, antiangiogenic therapy that could prevent tumor recurrence. Here, we characterize an experimental model that recapitulates the clinical dormancy of human tumors in mice. We demonstrate that these microscopic dormant cancers switch to the angiogenic phenotype at a predictable time. We further show that while angiogenic liposarcomas expand rapidly after inoculation of tumor cells in mice, nonangiogenic dormant liposarcomas remain microscopic up to one-third of the normal severe combined immune deficiency (SCID) mouse life span, although they contain proliferating tumor cells. Nonangiogenic dormant tumors follow a similar growth pattern in subcutaneous (s.c.) and orthotopic environments. Throughout the dormancy period, development of intratumoral vessels is impaired. In nonangogenic dormant tumors, small clusters of endothelial cells without lumens are observed early after tumor cell inoculation, but the nonangiogenic tumor cannot sustain these vessels, and they disappear within weeks. There is a concomitant decrease in microvessel density, and the nonangiogenic dormant tumor remains harmless to the host. In contrast, microvessel density in tumors increases rapidly after the angiogenic switch and correlates with rapid expansion of tumor mass. Both tumor types cultured in vitro contain fully transformed cells, but only cells from the nonangiogenic human liposarcoma secrete relatively high levels of the angiogenesis inhibitors thrombospondin-1 and TIMP-1. This model suggests that as improved blood or urine molecular biomarkers are developed, the microscopic, nonangiogenic, dormant phase of human cancer may be vulnerable to antiangiogenic therapy years before symptoms, or before anatomical location of a tumor can be detected, by conventional methods.
    The FASEB Journal 06/2006; 20(7):947-9. DOI:10.1096/fj.05-3946fje · 5.48 Impact Factor
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    ABSTRACT: In tissue-based assays, thymosin beta15 (Tbeta15) has been shown to correlate with prostate cancer (CaP) malignancy and with future recurrence. To be clinically effective, it must be shown that Tbeta15 is released by the tumor into body fluids in detectable concentrations. Toward this end, we have worked to develop a quantitative high-throughput assay that can accurately measure clinically relevant concentrations of Tbeta15 in human urine. Sixteen antibodies were raised against recombinant Tbeta15 and/or peptide conjugates. One antibody, having stable characteristics over the wide range of pH and salt concentrations found in urine and minimal cross-reactivity with other beta thymosins, was used to develop a competitive enzyme-linked immunosorbent assay (ELISA). Urinary Tbeta15 concentration was determined for control groups; normal (N = 52), prostate intraepithelial neoplasia (PIN, N = 36), and CaP patients; untreated (N = 7) with subsequent biochemical failure, radiation therapy (N = 17) at risk of biochemical recurrence. The operating range of the competition ELISA fell between 2.5 and 625 ng/mL. Recoveries exceeded 75%, and the intra- and inter-assay coefficients of variability were 3.3% and 12.9%, respectively. No cross-reactivity with other urine proteins was observed. A stable Tbeta15 signal was recovered from urine specimens stored at -20 degrees C for up to 1 year. At a threshold of 40 (ng/dL)/mug protein/mg creatinine), the assay had a sensitivity of 58% and a specificity of 94%. Relative to the control groups, Tbeta15 levels were greater than this threshold in a significant fraction of the CaP patients (P < 0.001), including 5 of the 7 patients who later experienced PSA recurrence. We have established an ELISA that is able to detect Tbeta15 at clinically relevant concentrations in urine from patients with CaP. The assay will provide a tool for future clinical trials to validate urinary Tbeta15 as a predictive marker for recurrent CaP.
    Clinical Biochemistry 07/2005; 38(6):558-71. DOI:10.1016/j.clinbiochem.2005.01.015 · 2.23 Impact Factor
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    ABSTRACT: Additional prostate cancer (CaP) biomarkers are needed to increase the accuracy of diagnosis and to identify patients at risk of recurrence. In tissue-based assays, thymosin beta15 (Tbeta15) has been linked to an aggressive CaP phenotype and correlated with future tumor recurrence. We hypothesized that Tbeta15 may have clinical utility in biological fluids. Tbeta15 was measured in urine from CaP patients; untreated (N = 61), prostatectomy (RP, N = 46), androgen deprivation therapy (ADT, N = 14) and control groups; normal (N = 52), genitourinary carcinoma (N = 15), non-malignant prostate disease (N = 81), and other urology (N = 73). We evaluated the utility of urinary Tbeta15 for CaP diagnosis, alone or in combination with prostate-specific antigen (PSA), and the relationship to CaP progression. A normal threshold of 40 (ng/dl)/(mug_protein/mg_creatinine) was defined using receiver operating characteristic analysis and marked the 19th centile for age-matched controls. The proportion of untreated CaP patients with urinary Tbeta15 above the threshold was significantly higher than normal and genitourinary disease controls (P < 0.001). RP caused urinary Tbeta15 to drop significantly (P = 0.005). Pre-surgery Tbeta15 concentrations greater than the normal threshold may confer greater risk of CaP recurrence. Relative to normal controls, patients receiving ADT for aggressive CaP were 12 times more likely to have elevated urinary Tbeta15 (P = 0.001, 95% CI = 2.8, 51.8). Combining PSA and Tbeta15 (PSA > 4, or PSA > 2.5, Tbeta15 > 40, or PSA = 2.5, Tbeta15 > 90) provided the same sensitivity as a 2.5 ng/ml PSA cutoff, but markedly improved diagnostic specificity. We report that Tbeta15 is a urinary biomarker for CaP and suggest that Tbeta15, in combination with PSA, can be used to improve both the sensitivity and specificity of CaP diagnosis.
    The Prostate 07/2005; 64(2):116-27. DOI:10.1002/pros.20202 · 3.57 Impact Factor
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    ABSTRACT: Mammalian cells express several isoforms of β-thymosin, a major actin monomer sequestering factor, including thymosins β4, β10, and β15. Differences in actin-binding properties of different β-thymosin family members have not been investigated. We find that thymosin β15 binds actin with a 2.4-fold higher affinity than does thymosin β4. Mutational analysis was performed to determine the amino acid differences in thymosin β15 that specify its increased actin-affinity. Previous work with thymosin β4 identified an α-helical domain, as well as a conserved central motif, as crucial for actin binding. Mutational analysis confirms that these domains are also vital for actin binding in thymosin β15, but that differences in these domains are not responsible for the variation in actin-binding properties between thymosins β4 and β15. Truncation of the unique C-terminal residues in thymosin β15 inhibits actin binding, suggesting that this domain also has an important role in mediating actin-binding affinity. Replacement of the 10 C-terminal amino acids of thymosin β15 with those of thymosin β4 did, however, reduce the actin-binding affinity of the hybrid relative to thymosin β15. Similarly, replacement of the thymosin β4 C-terminal amino acids with those of thymosin β15 led to increased actin binding. We conclude that functional differences between closely related β-thymosin family members are, in part, specified by the C-terminal variability between these isoforms. Such differences may have consequences for situations where β-thymosins are differentially expressed as in embryonic development and in cancer. J. Cell. Biochem. 77:277–287, 2000. © 2000 Wiley-Liss, Inc.
    Journal of Cellular Biochemistry 05/2000; 77(2):277-287. DOI:10.1002/(SICI)1097-4644(20000501)77:23.0.CO;2-Q · 3.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mammalian cells express several isoforms of beta-thymosin, a major actin monomer sequestering factor, including thymosins beta4, beta10, and beta15. Differences in actin-binding properties of different beta-thymosin family members have not been investigated. We find that thymosin beta15 binds actin with a 2.4-fold higher affinity than does thymosin beta4. Mutational analysis was performed to determine the amino acid differences in thymosin beta15 that specify its increased actin-affinity. Previous work with thymosin beta4 identified an alpha-helical domain, as well as a conserved central motif, as crucial for actin binding. Mutational analysis confirms that these domains are also vital for actin binding in thymosin beta15, but that differences in these domains are not responsible for the variation in actin-binding properties between thymosins beta4 and beta15. Truncation of the unique C-terminal residues in thymosin beta15 inhibits actin binding, suggesting that this domain also has an important role in mediating actin-binding affinity. Replacement of the 10 C-terminal amino acids of thymosin beta15 with those of thymosin beta4 did, however, reduce the actin-binding affinity of the hybrid relative to thymosin beta15. Similarly, replacement of the thymosin beta4 C-terminal amino acids with those of thymosin beta15 led to increased actin binding. We conclude that functional differences between closely related beta-thymosin family members are, in part, specified by the C-terminal variability between these isoforms. Such differences may have consequences for situations where beta-thymosins are differentially expressed as in embryonic development and in cancer.
    Journal of Cellular Biochemistry 04/2000; 77(2):277-87. · 3.37 Impact Factor

Publication Stats

182 Citations
30.52 Total Impact Points

Institutions

  • 2007
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2005–2007
    • Harvard Medical School
      • Department of Surgery
      Boston, Massachusetts, United States
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 2006
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States