X Zhu

University of Washington Seattle, Seattle, WA, United States

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Publications (10)34.11 Total impact

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    ABSTRACT: Scatter factor (SF), also known as hepatocyte growth factor (HGF), has been shown to induce proliferation, scattering and invasiveness in human prostate cancer cell lines. In this study we determined the serum level of SF-HGF in men with metastatic prostate cancer compared to those with localized prostate cancer and without prostate cancer. Serum samples were obtained from men with biopsy proved adenocarcinoma of the prostate and radiographic evidence of metastatic disease, those with biopsy proved adenocarcinoma of the prostate and clinically localized disease, and those with negative sextant prostate biopsies. Serum SF-HGF was determined using a commercially available enzyme-linked immunosorbent assay kit. Of the 108 men enrolled in our study 52 had negative sextant biopsies, 36 had clinically localized cancer and 20 had metastatic disease. The serum level in men with metastatic disease was significantly elevated (mean 2,117 pg./ml., range 820 to 6,403) compared to that in men with localized cancer and without prostate cancer (mean 974 pg./ml., range 437 to 2,132 and 700, range 272 to 1,875, respectively, p = 9.5 x 10(-15)). Logistic regression analysis demonstrated that the association of ln (SF-HGF) with prostate cancer persisted after controlling for patient age and ln (prostate specific antigen) (p = 3.1 x 10(-4)). Serum SF-HGF is increased in men with metastatic prostate cancer. SF-HGF levels are associated with metastatic prostate cancer independent of the prostate specific antigen level and patient age. These data imply that SF-HGF may be an important serum marker for prostate cancer.
    The Journal of Urology 05/2001; 165(4):1325-8. · 3.75 Impact Factor
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    ABSTRACT: Spindle cell sarcomas often present the surgical pathologist with a considerable diagnostic challenge. Malignant peripheral nerve sheath tumor, leiomyosarcoma, fibrosarcoma, and monophasic synovial sarcoma may all appear similar histologically. The application of ancillary diagnostic modalities, such as immunohistochemistry and electron microscopy, may be helpful in the differentiation of these tumors, but in cases in which these adjunctive techniques fail to demonstrate any more definitive evidence of differentiation, tumor categorization may remain difficult. Cytogenetic and molecular genetic characterization of tumors have provided the basis for the application of molecular assays as the newest components of the diagnostic armamentarium. Because the chromosomal translocation t(X;18) has been observed repeatedly in many synovial sarcomas, it has been heralded as a diagnostic hallmark of synovial sarcoma. To formally test the specificity of this translocation for the diagnosis of synovial sarcoma, RNA extracted from formalin-fixed, paraffin-embedded tissue from a variety of soft tissue and spindle cell tumors was evaluated for the presence of t(X;18) by reverse transcriptase-polymerase chain reaction. Although 85% of the synovial sarcomas studied demonstrated t(X;18), 75% of the malignant peripheral nerve sheath tumors in our cohort also demonstrated this translocation. We conclude that the translocation t(X;18) is not specific to synovial sarcoma and discuss the implications of the demonstration of t(X;18) in a majority of malignant peripheral nerve sheath tumors.
    Modern Pathology 01/2001; 13(12):1336-46. · 5.25 Impact Factor
  • X Zhu, P A Humphrey
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    ABSTRACT: Scatter factor (hepatocyte growth factor) (SF/HGF) is a multifunctional polypeptide growth factor that has been implicated in tumor proliferation, angiogenesis, invasiveness, and metastasis. Little is known of the expression of SF/HGF in human prostatic carcinoma. The aims of this investigation were to quantitate the level of SF/HGF expression in benign versus malignant human prostatic tissues and to assess regulation of SF/HGF expression by human prostatic stromal myofibroblasts. We determined the level of SF/HGF expression in 10 human prostatic tissue samples (5 benign, 5 carcinoma) by Western blot analysis. Five purified growth factors-basic fibroblast growth factor (bFGF), interleukin-1beta (IL-1beta), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and endothelial growth factor (EGF)-were tested for their capacity to induce SF/HGF expression by a human prostatic stromal myofibroblastic cell line, as assessed by enzyme-linked immunosorbent assay. Supernatant from the normal PrEC prostatic epithelial cell line and the DU 145 carcinoma cell line were assayed for SF/HGF-inducing activity. SF/HGF exhibited a mean fourfold overexpression in carcinoma tissues compared with benign prostatic tissue. Significant stimulation of SF/HGF expression by prostatic stromal myofibroblasts was detected for IL-1beta (8.1-fold), PDGF (6.2-fold), bFGF (4.0-fold), VEGF (3. 7-fold), and EGF (2.9-fold). DU 145-conditioned media, but not the PrEC-conditioned media, contained SF/HGF-inducing activity, which was determined to include IL-1beta, bFGF, and PDGF by antibody-blocking experiments. SF/HGF is overexpressed in human prostatic carcinoma tissues. Prostatic carcinoma cell stimulation of SF/HGF expression by adjacent benign myofibroblastic cells as a type of epithelial-stromal paracrine interaction could potentially influence prostatic carcinoma cell behaviors.
    Urology 01/2001; 56(6):1071-4. · 2.42 Impact Factor
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    ABSTRACT: Differentiating desmoplastic small round cell tumor (DSRCT) from another similar small round cell tumor of childhood, the Ewing sarcoma/primitive neuroectodermal tumor (EWS/PNET), can be difficult because morphologic and immunohistochemical features overlap. We studied the predictive value of immunohistochemistry with an antibody to the C-terminal region of the Wilms tumor (WT1) protein for differentiating DSRCT from EWS/PNET in 24 malignant small round cell tumors that had been previously diagnosed as DSRCT or EWS/PNET by standard methods. We performed reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in cases with available tissue as a confirmatory measure: 6 of 13 DSRCTs were informative by RT-PCR, and 6 of 6 showed an EWS-WT1 fusion; all 13 DSRCTs showed strong, definitive nuclear staining with the WT1 antibody. All 11 EWS/PNETs were WT1 antibody negative; 7 of 11 cases classified as EWS/PNET were informative by RT-PCR, and 7 of 7 showed an EWS-FLI-1 fusion. For cases in which the morphologic and immunohistochemical features are consistent with a diagnosis of DSRCT, WT1 antibody staining predicts the EWS-WT1 translocation with high sensitivity and specificity and is, therefore, useful for differentiating DSRCT from EWS/PNET when genetic information is unavailable.
    American Journal of Clinical Pathology 10/2000; 114(3):345-53. · 2.88 Impact Factor
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    ABSTRACT: Atypical adenomatous hyperplasia (AAH) of the prostate, a small glandular proliferation, is a putative precursor lesion to prostate cancer, in particular to the subset of well-differentiated carcinomas that arise in the transition zone, the same region where AAH lesions most often occur. Several morphological characteristics of AAH suggest a relationship to cancer; however, no definitive evidence has been reported. In this study, we analyzed DNA from 25 microdissected AAH lesions for allelic imbalance as compared to matched normal DNA, using one marker each from chromosome arms 1q, 6q, 7q, 10q, 13q, 16q, 17p, 17q, and 18q, and 19 markers from chromosome 8p. We observed 12% allelic imbalance, with loss only within chromosome 8p11-12. These results suggest that genetic alterations in transition zone AAH lesions may be infrequent. This genotypic profile of AAH will allow for comparisons with well-differentiated carcinomas in the transition zone of the prostate.
    American Journal Of Pathology 10/1999; 155(3):967-71. · 4.60 Impact Factor
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    ABSTRACT: Triton tumors are rare variants of malignant peripheral nerve sheath tumor (MPNST) with muscle differentiation, often seen in patients with neurofibromatosis 1 (NF1). Individuals affected with NF1 harbor mutations in the NF1 tumor suppressor gene and develop neurofibromas and MPNSTs. The NF1 gene is expressed in Schwann cells and its expression is lost in schwannian neoplasms, suggesting a role in malignant development. Separately, there is evidence that p53 suppressor gene mutations are involved in MPNSTs. To determine the role of the NF1 and p53 genes in the development of the malignant Triton tumor we examined 2 such tumors, 1 from a 3-year-old boy without clinical manifestations of NF1 and another from a 24-year-old man with NF1. Histological analysis of these tumors showed both neural and muscle differentiation with S-100 and desmin immunoreactivity, respectively. Reverse transcribed RNA polymerase chain reaction (RT-PCR) of NF1 mRNA showed NF1 expression in the sporadic tumor. Strong nuclear immunoreactivity for p53 was observed throughout the malignant population in both tumors. This was confirmed by loss of heterozygosity for p53 in the non-NF1 patient, suggesting that p53 is involved in both hereditary and sporadic Triton tumors. The finding of preserved NF1 gene expression in the non-NF1-related Triton tumor suggests that different genetic events predispose to the development of this rare neoplasm in sporadic cases.
    Human Pathlogy 09/1999; 30(8):984-8. · 2.84 Impact Factor
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    ABSTRACT: Determination of the biologic potential of cutaneous lymphoid infiltrates may be difficult by standard histologic or immunohistologic examination. The polymerase chain reaction (PCR) has been used to document clonal rearrangements of the immunoglobulin heavy chain gene in paraffin-embedded fixed tissues. To explore the value of PCR in evaluation of cutaneous lymphoid infiltrates, 93 archival nonmycotic lymphoid lesions (28 small or mixed lymphocytic lymphomas, 15 large cell lymphomas, 40 benign infiltrates, and 10 with atypical features) were analyzed. These cases had been previously immunophenotyped on paraffin sections, and clinical follow-up from 7 to 20 years was gathered. DNA products were generated using a seminested PCR technique, separated by 5% polyacrylamide gel electrophoresis, stained with ethidium bromide, and visualized under UV light. Cases with a 100- to 120-base pair band were scored as positive. Of the 28 small or mixed cell lymphomas, 23 had a B-cell immunophenotype or consisted of a mixture of B and T cells; of these, seven (30%) demonstrated a monoclonal pattern, and three (13%) were indeterminate. Twelve large cell cases were B-cell or mixed; five (42%) of these were positive for a monoclonal band, while four (33%) were indeterminate. None of five T-cell small cell or three T-cell large cell lymphomas demonstrated a monoclonal band. In contrast, 39 of the 40 benign cases were T-cell predominant or mixed lesions. Nevertheless, 18 of these 40 cases on initial testing suggested possible monoclonality. Six were indeterminate, and 12 demonstrated apparent monoclonal bands, of which four were reproducible on repeat testing. No histologic or clinical features of lymphoma were present in 17 of these 18 cases, suggesting that they represent false-positive results. Most of the latter lesions showed sparse perivascular infiltrates, with very few B cells. This suggests that amplification of the immunoglobulin heavy chain gene from a small number of lymphocytes may produce a monoclonal band. In summary, PCR may provide adjunct information about clonality in selected lymphoid skin lesions, but is rather insensitive in this setting. Such data must be carefully considered in the context of the histologic, immunohistologic, and clinical findings, particularly when assessing sparse infiltrates, because of the potential for false-positive results.
    American Journal of Clinical Pathology 08/1997; 108(1):60-8. · 2.88 Impact Factor
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    ABSTRACT: Primitive neuroectodermal tumor (PNET), the second most common type of sarcoma in the first two decades of life, rarely presents as an organ-based neoplasm. Rather, it is seen typically in the soft tissues of the chest wall and paraspinal region. We report a case of primary PNET of the kidney in a 17-year-old girl who presented with abdominal pain, hematuria, and an abdominal mass. Nodules and sheets of monotonous-appearing primitive round cells and the formation of rosettes focally were the principal microscopic features. The tumor cells were uniformly immunoreactive for vimentin, cytokeratin, neuron-specific enolase, and 013 (CD99). In addition, the characteristic translocation of PNET and Ewing sarcoma, t(11;22)(q24;q12), was detected by polymerase chain reaction (PCR). Eight previous examples of renal PNET have been reported in the literature in the past 2 years, but only three of these cases have had complete immunohistochemical evaluation with the demonstration of 013 positivity. To our knowledge the present case is the only one to date demonstrating the recurrent translocation t(11;22)(q24;q12) by PCR. Assuming that the previous cases in the literature are bona fide examples of PNET, the kidney may be another site of predilection for this usual soft-tissue neoplasm. We are once again confronted with the dilemma about the nature of the progenitor cell.
    American Journal of Surgical Pathology 04/1997; 21(3):354-9. · 4.87 Impact Factor
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    ABSTRACT: The type III deletion-mutant gene for the epidermal growth factor receptor (EGFRvIII) is frequently expressed in glioblastomas and in breast and non-small cell lung carcinomas. To understand its contribution to the malignant phenotype in humans, we transfected NR6 cells with the mammalian vector pH beta APr-1-neo containing cDNA for either EGFRvIII or wild-type EGFR. Western blot analyses showed that NR6 transfected with wild-type EGFR (NR6W) contained a normal-sized protein (170 kilodaltons); cells transfected with EGFRvIII (NR6M) contained a truncated protein (145 kilodaltons). NR6W cells demonstrated a saturation binding curve with 125I-labeled EGF (affinity, 1.8 x 10(8); r2 = 0.96). NR6M cells, however, showed a low but consistent level of 125I-labeled EGF binding (affinity, 4 x 10(7); r2 = 0.99) compared with NR6, which lacked binding. The population doubling time was shorter for NR6M (0.64 days) than for NR6W (1.1 days) and NR6V (2.27 days). Soft agar focus formation assay by NR6M was 4- to 5-fold higher than that by NR6W. In nude mice, NR6M (1 x 10(7) cells), without exogenous ligand, formed tumors within 12 days; no tumors were observed over 90 days in mice receiving identical doses of NR6W, NR6V, or NR6 cells. EGF stimulated autophosphorylation of receptor in NR6W (4- to 9-fold) but caused only slight (1.8- to 1.9-fold) to no enhancement in NR6M. Further, there was no difference in constitutive tyrosine kinase activity between NR6M and NR6W. Our results clearly indicate that EGFRvIII functions as an oncoprotein, but its intrinsic tyrosine kinase activity may not be responsible for its biological function.
    Cell growth & differentiation: the molecular biology journal of the American Association for Cancer Research 11/1995; 6(10):1251-9.
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    ABSTRACT: Hepatocyte growth factor (scatter factor) and its receptor, the c-met proto-oncogene product (c-MET), have been implicated in embryogenesis, tissue reorganization, and tumor progression. Little is known, however, of the expression and functional significance of these molecules in prostatic cells and tissue. In this investigation, we assessed the expression of hepatocyte growth factor (HGF) and c-MET in prostatic tissues and cell lines and also determined the effect of purified recombinant HGF on cell proliferation and scattering of prostatic carcinoma cell lines. HGF was expressed by human prostatic stromal myofibroblasts in primary culture but not by three human prostatic carcinoma cell lines (LNCaP, DU 145, and PC-3) as assessed by Northern blot analysis. HGF was also detected by reverse transcriptase-polymerase chain reaction in both benign and malignant tissues from radical prostatectomy specimens. c-MET transcripts were identified by Northern blot in two androgen-insensitive human prostatic carcinoma cell lines (DU 145 and PC-3) but not the androgen-sensitive LNCaP cell line. Additional evidence of linkage of androgen responsiveness and c-MET was provided by experiments in which androgen deprivation of normal rat prostates via castration produced a marked up-regulation of c-MET expression as determined by Northern blot and immunohistochemistry. c-MET protein was detected by immunohistochemical analysis in a substantial percentage (58 of 128 or 45%) of prostatic carcinomas and was found more often in metastatic growths of human prostatic carcinoma (15 of 20 patients) compared with primary tumors (43 of 108 patients; P < 0.005). Moreover, in Dunning R-3327 rat prostatic carcinoma cell lines, c-MET expression was highest in the androgen-insensitive subline with the highest metastatic capacity. Purified recombinant human HGF induced dose-dependent cellular proliferation and scattering in the DU 145 carcinoma cell line. These data indicate that HGF may function in the prostate gland as a paracrine growth factor, with synthesis by stromal cells and with biological target cells being the epithelial cells. Expression of the HGF receptor, c-MET, is up-regulated by androgen deprivation and c-MET appears to be preferentially expressed on androgen-insensitive, metastatic cells, suggesting a possible linkage of c-MET expression with prostatic carcinoma progression.
    American Journal Of Pathology 08/1995; 147(2):386-96. · 4.60 Impact Factor