Melanoma: Wang S

Niederkorn JY, Wang S. · Department of Opthamology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9057, USA. · Ocul Immunol Inflamm. · Pubmed #15835077 No free full text.

Abstract: The immune surveillance hypothesis was introduced over 30 years ago and proposed that neoplasms express novel antigens that subjected them to immune detection and elimination. In order for immune surveillance to be effective in controlling neoplasms, two requirements must be satisfied: 1) the tumor must arise in a body site that permits the induction the full array of immune responses and 2) the immune elements generated must have unfettered access to the tumor and be able to express their entire range of effector functions at the tumor site. The unique immunologic and anatomic features of the eye prevent the induction and expression of conventional immunity--a phenomenon known as 'immune privilege'. Although ocular immune privilege represents a theoretical obstacle to immune surveillance, some highly immunogenic intraocular tumors can circumvent immune privilege and undergo immune rejection. Uveal melanoma is the most common intraocular malignancy in adults, yet it occurs with a frequency that is no higher than neoplasms arising in conventional bodies. The presence of either tumor-infiltrating lymphocytes (TIL) or tumor-infiltrating macrophages (TIM) is associated with poor prognosis in uveal melanoma patients and suggests that some immune responses to intraocular tumors might exacerbate, rather than mitigate, tumor progression. Although counterintuitive, this proposition is consistent with the 'immune stimulation' hypothesis of tumor progression offered by Richmond Prehn over thirty years ago. It remains to be ascertained if immune stimulation affects the malignancy of ocular tumors, but it represents an intriguing explanation for the paradoxes of uveal melanoma.

Lewis JJ, Janetzki S, Schaed S, Panageas KS, Wang S, Williams L, Meyers M, Butterworth L, Livingston PO, Chapman PB, Houghton AN. · Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. · Int J Cancer. · Pubmed #10897045 No free full text.

Abstract: The lack of reproducible, quantitative assays for T-cell responses has been a limitation in the development of cancer vaccines to elicit T-cell immunity. We utilized the Elispot assay, which allows a quantitative and functional assessment of T cells directed against specific peptides after only brief in vitro incubations. CD8(+) T-cell reactivity was determined with an interferon (IFN)-gamma Elispot assay detecting T cells at the single cell level that secrete IFN-gamma. We studied both healthy individuals and patients with melanoma. Healthy HLA-A*0201-positive individuals showed a similar mean frequency of CD8(+) cells recognizing a tyrosinase peptide, YMDGTMSQV, when compared with melanoma patients prior to immunization. The frequencies of CD8(+) cells recognizing the tyrosinase peptide remained relatively constant over time in healthy individuals. Nine HLA-A*0201-positive patients with stage IV metastatic melanoma were immunized intradermally with the tyrosinase peptide together with the immune adjuvant QS-21 in a peptide dose escalation study with 3 patients per dose group. Two patients demonstrated a significant increase in the frequency of CD8(+) cells recognizing the tyrosinase peptide during the course of immunization, from approx. 1/16,000 CD8(+) T cells to approx. 1/4,000 in the first patient and from approx. 1/14,000 to approx. 1/2,000 in the second patient. These results demonstrate that modest expansion of peptide-specific CD8(+) T cells can be generated in vivo by immunization with peptide plus QS-21 in at least a subset of patients with melanoma.

Chernoff KA, Bordone L, Horst B, Simon K, Twadell W, Lee K, Cohen JA, Wang S, Silvers DN, Brunner G, Celebi JT. · Departments of Dermatology and Pathology and Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, USA. · Clin Cancer Res. · Pubmed #19509136 No free full text.

Abstract: PURPOSE: Gain-of-function mutations in BRAF, NRAS, or KIT are associated with distinct melanoma subtypes with KIT mutations and/or copy number changes frequently observed among melanomas arising from sun-protected sites, such as acral skin (palms, soles, and nail bed) and mucous membranes. GAB2 has recently been implicated in melanoma pathogenesis, and increased copy numbers are found in a subset of melanomas. We sought to determine the association of increased copy numbers of GAB2 among melanoma subtypes in the context of genetic alterations in BRAF, NRAS, and KIT. EXPERIMENTAL DESIGN: A total of 85 melanomas arising from sun-protected (n = 23) and sun-exposed sites (n = 62) were analyzed for copy number changes using array-based comparative genomic hybridization and for gain-of-function mutations in BRAF, NRAS, and KIT. RESULTS: GAB2 amplifications were found in 9% of the cases and were associated with melanomas arising from acral and mucosal sites (P = 0.005). Increased copy numbers of the KIT locus were observed in 6% of the cases. The overall mutation frequencies for BRAF and NRAS were 43.5% and 14%, respectively, and were mutually exclusive. Among the acral and mucosal melanomas studied, the genetic alteration frequency was 26% for GAB2, 13% for KIT, 30% for BRAF, and 4% for NRAS. Importantly, the majority of GAB2 amplifications occurred independent from genetic events in BRAF, NRAS, and KIT. CONCLUSIONS: GAB2 amplification is critical for melanomas arising from sun-protected sites. Genetic alterations in GAB2 will help refine the molecular classification of melanomas.

Shinozaki Y, Wang S, Miyazaki Y, Miyazaki K, Yamada H, Yoshikai Y, Hara H, Yoshida H. · Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan. · Int J Cancer. · Pubmed #19089917 No free full text.

Abstract: Interleukin (IL-) 27 is a member of IL-12 cytokine family with Th1-promoting and anti-inflammatory effects. IL-27 has been shown to facilitate tumor-specific cytotoxic T lymphocyte (CTL) induction against various tumors. However, IL-27 suppresses cytokine production of lymphocytes and antigen-presenting function of dendritic cells (DCs). To examine the in vivo role of IL-27 in generation of anti-tumor immunity, we examined IL-27-mediated antitumor-effects using WSX-1 (IL-27 receptor alpha chain)-deficient (WSX-1(-/-)) mice. In WSX-1(-/-) mice inoculated with B16 melanoma cells, tumor growth was higher than in wild-type (WT) mice. Accordingly, tumor-specific CTL generation was lower in WSX-1(-/-) mice than in WT mice. CTL induction in WSX-1(-/-) mice was not restored by transfer of WT DCs pulsed with TRP2 peptide, indicating that IL-27 is directly required for generation of tumor-specific CTLs. However, when transferred into tumor-bearing mice, WSX-1(-/-) DCs pulsed with TRP2 peptide was more potent than WT DCs in tumor growth inhibition and generation of CTLs, indicating suppressive effects of IL-27 on DC function. Finally, the combination of WT CD8(+) T cells and KO DCs is more potent in generation of antigen-specific CTLs than any other combinations. Expression of perforin gene and percentages of tumor-specific CD8(+) T cells were also the highest in the combination of WT CD8+ T cells and WSX-1(-/-) DCs. It was thus revealed that IL-27 promotes CTL generation while suppressing DC function during generation of tumor immunity. The combination of WT T cells and IL-27 signal-defective DCs may have therapeutic potential against tumors.

Wang S, Dhawan AP. · Department of Electrical & Computer Engineering, New Jersey Institute of Technology, United States. · Comput Med Imaging Graph. · Pubmed #18585895 No free full text.

Abstract: Multi-spectral optical imaging of skin and skin-lesions has been of significant interest for various biomedical applications. A multi-spectral optical imaging instrument called Nevoscope has been developed to acquire images of skin and skin-lesion through trans-illumination. Nevoscope based multi-spectral trans-illumination imaging is aimed at characterization of skin-lesions for early diagnosis of skin-cancers by reconstructing distributions of melanin and blood. Conventional approaches usually involve dividing the field of view into a number of voxels and assuming constant optical properties in each voxel. The optical properties are reconstructed in terms of measurements at multiple wavelengths and the distribution of melanin and blood are subsequently calculated. However, since the inverse problem is generally an ill-posed and under-determined one, it is hard to get quantitatively accurate reconstruction. In this paper, a shape-based multi-constrained reconstruction algorithm is presented, which uses a genetic algorithm based optimization methods to find the best possible reconstruction solution. A skin-lesion such as melanoma is modeled as melanin and blood parts, which are delineated by two cubic tensor-product B-spline surfaces. This reduces the number of unknowns to a few control parameters of the surfaces. The parameters are then coded into a genetic algorithm to find a solution through global optimization. Reasonable constraints are incorporated into the genetic algorithm to stabilize the solution. Results of reconstructions of melanin and blood parts are presented for simulated lesions using multi-spectral wavelengths at 580nm and 800nm.

Sun B, Zhang S, Zhang D, Yin X, Wang S, Gu Y, Wang Y. · Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin 300060, PRChina. · Exp Biol Med (Maywood). · Pubmed #17959842 links to  free full text

Abstract: To examine the effects of doxycycline on invasion-related protein expression and proliferation of melanoma cells and to evaluate its effect on microcirculation patterns in melanoma, we injected murine melanoma B16 cell suspensions into the groin areas of C57BL/6 mice that were randomly divided into treatment and control groups. Eight days after tumor cell injection, we administered doxycycline intraperitoneally (ip) at a dose of 0.15 mg/g/day in the treatment group and administered a physiological saline solution to the control group. Animals were sacrificed on Day 22, and we removed and weighed tumor masses and counted the numbers of vasculogenic mimicry (VM) and endothelium-dependent vessels. Immunohistochemical staining was used to analyze the expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), and proliferating cell nuclear antigen (PCNA). We prepared protein extracts of the tumors, and we examined the activity of MMP-2 and MMP-9 in different groups by gelatin zymography. Real-time polymerase chain reaction (PCR) was used to detect MMP-2 and MMP-9 mRNA level in the fresh tumor tissue. Doxycycline treatment partly suppressed the growth of engrafted B16 melanoma, with an inhibition rate of 35.63%. There were more VM and endothelium-dependent vessels in the control group than in the treatment group. The expression level of MMP-2 and MMP-9 in the treatment group was lower than that in the control group (P < 0.01, P < 0.05). Compared with the control group, VEGF expression was increased with doxycycline treatment. The enzyme activities of MMP-9, active-MMP-2, and MMP-2/pro-MMP-2 in the treatment group were lower than those in the control group (P < 0.01). MMP-2 and MMP-9 mRNA levels in the treatment group were also lower than those in the control group were. Doxycycline inhibits the growth of engrafted melanoma and results in reduced expression of MMP-2, MMP-9, and VM formations.

Kou G, Gao J, Wang H, Chen H, Li B, Zhang D, Wang S, Hou S, Qian W, Dai J, Zhong Y, Guo Y. · International Joint Cancer Institute and College of Pharmacy, Second Military Medical University, New Library Building West 10th-11th Floor, 800 Xiang Yin Road, Shanghai 200433, People's Republic of China. · J Biochem Mol Biol. · Pubmed #17927907 links to  free full text

Abstract: The purpose of this study was to develop paclitaxel-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles coated with cationic SM5-1 single-chain antibody (scFv) containing a polylysine (SMFv-polylys). SM5-1 scFv (SMFv) is derived from SM5-1 monoclonal antibody, which binds to a 230 kDa membrane protein specifically expressed on melanoma, hepatocellular carcinoma and breast cancer cells. SMFv-polylys was expressed in Escherichia coli and purified by cation-exchange chromatography. Purified SMFv-polylys was fixed to paclitaxel-loaded PLGA nanoparticles to form paclitaxel-loaded PLGA nanoparticles coated with SMFv-polylys (Ptx-NP-S). Ptx-NP-S was shown to retain the specific antigen-binding affinity of SMFv-polylys to SM5-1 binding protein-positive Ch-hep-3 cells. Finally, the cytotoxicity of Ptx-NP-S was evaluated by a non-radioactive cell proliferation assay. It was demonstrated that Ptx-NP-S had significantly enhanced in vitro cytotoxicity against Ch-hep-3 cells as compared with non-targeted paclitaxel-loaded PLGA nanoparticles. In conclusion, our results suggest that cationic SMFv-polylys has been successfully generated and may be used as targeted ligand for preparing cancer-targeted nanoparticles.

Li N, Qin H, Li X, Zhou C, Wang D, Ma W, Lin C, Zhang Y, Wang S, Zhang S. · Department of Immunology, Cancer Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. · Immunol Lett. · Pubmed #17913245 No free full text.

Abstract: In this study, we demonstrate that an effective immune response against prostate tumors in mouse tumor model can be elicited using a strategy that combines CTLA-4 blockade and pSLC-3P-Fc-modified tumor cell vaccine (named B16F10-SLC-3P-Fc). Treatment of B16F10-3P-bearing mice resulted in a significant reduction in tumor incidence as assessed 2 months after treatment. In vivo Ab depletion confirmed that the antitumor effect was primarily CD8+ T cells and CD4+ T lymphocytes were required for the induction of CD8+ CTL response in B16F10-SLC-3P-Fc+anti-CTLA-4 mAb-immunized mice. Moreover, mice that were cured of an established tumor were protected against a rechallenge with the same tumor for at least 4 months, suggesting the generation of memory responses. Adoptive transfer experiments further indicate that antitumor reactivity can be transferred to naïve mice by splenocytes. These findings demonstrate that this combinatorial treatment can elicit a potent anti-tumor immune response and suggest potential of this approach for treatment of prostate cancer.

Marín YE, Wall BA, Wang S, Namkoong J, Martino JJ, Suh J, Lee HJ, Rabson AB, Yang CS, Chen S, Ryu JH. · Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA. · Melanoma Res. · Pubmed #17885582 No free full text.

Abstract: Melanoma, the most deadly form of skin cancer, is very aggressive and resistant to present therapies. The transcription factor nuclear factor-kappa B (NF-kappaB) has been reported to be constitutively active in many types of cancer. Constitutively active NF-kappaB seen in melanoma likely plays a central role in cell survival and growth. We have established and characterized novel cell lines from our murine melanoma model. Here we report the constitutive activity of NF-kappaB in these melanoma-derived cells, as shown by electrophoretic mobility shift assay and reporter assays. We hypothesized that agents that inhibit NF-kappaB may also inhibit cell proliferation and may induce apoptosis in such melanoma cells. Curcumin has been shown to inhibit NF-kappaB activity in several cell types. In our system, curcumin selectively inhibited growth of melanoma cells, but not normal melanocytes. Curcumin induced melanoma cells to undergo apoptosis, as shown by caspase-3 activation, inversion of membrane phosphatidyl serine, and increases in cells in the sub-G1 phase. A curcumin dose-dependent inhibition of NF-kappaB-driven reporter activity correlated with decreased levels of phospho-IkappaBalpha, and decreased expression of NF-kappaB-target genes COX-2 and cyclin D1. This study demonstrates that the use of cells from our model system can facilitate studies of signaling pathways in melanoma. We furthermore conclude that curcumin, a natural and safe compound, inhibits NF-kappaB activity and the expression of its downstream target genes, and also selectively induces apoptosis of melanoma cells but not normal melanocytes. These encouraging in-vitro results support further investigation of curcumin for treatment of melanoma in vivo.

Chen PW, Mellon JK, Mayhew E, Wang S, He YG, Hogan N, Niederkorn JY. · Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9057, USA. · Exp Eye Res. · Pubmed #17870068 links to  free full text

Abstract: The enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes degradation of tryptophan, an essential amino acid required for lymphocyte activation and proliferation. Many tumors express IDO which implies that it acts as a mechanism to evade T cell-mediated immune attack, and also to establish an immunosuppressive tumor microenvironment. The purpose of this study was to determine whether primary and metastatic uveal melanoma expressed the IDO gene and whether uveal melanoma cells could deplete tryptophan. In situ expression of IDO in primary uveal melanoma from tumor bearing eyes and metastatic uveal melanoma liver tissues was determined by immunohistostaining with IDO-specific antibody. Reverse transcription PCR was used to assess IDO gene transcription by primary and metastatic uveal melanoma cell lines. IDO protein expression was determined by Western blot of uveal melanoma cell protein lysate. IDO catalytic activity was assessed by measuring the presence of kynurenine, a product generated by tryptophan degradation, in uveal melanoma culture supernatants. Primary uveal melanoma from tumor-bearing eyes and metastatic uveal melanoma from the liver did not express IDO in situ. IDO was not constitutively expressed in either primary or metastatic uveal melanoma cell lines. However, stimulation of primary and metastatic uveal melanoma cell cultures with interferon-gamma (IFN-gamma) universally upregulated both IDO gene and protein expression. Culture supernatants from IFN-gamma treated primary and metastatic uveal melanoma cell cultures contained elevated levels of kynurenine. Addition of the IDO inhibitor 1-methyl dl-tryptophan significantly diminished kynurenine levels in IFN-gamma treated uveal melanoma cell cultures. The results from this study suggest that IFN-gamma inducible IDO upregulation by primary and metastatic uveal melanoma may generate a local immune privileged microenvironment to promote escape from T cell-mediated immune surveillance.

Wolter KG, Verhaegen M, Fernández Y, Nikolovska-Coleska Z, Riblett M, de la Vega CM, Wang S, Soengas MS. · Department of Dermatology, University of Michigan, Comprehensive Cancer Center, Ann Arbor, MI 48109, USA. · Cell Death Differ. · Pubmed #17541428 links to  free full text

Abstract: Melanoma cells depend on sustained proteasomal function for survival. However, bortezomib, the first proteasome inhibitor in clinical use, is not sufficient to improve the poor prognosis of metastatic melanoma patients. Since the proteasome is also expressed in all normal cell compartments, it is unclear how to enhance the efficacy of bortezomib without exacerbating secondary toxicities. Here, we present pharmacological and genetic analyses of mechanisms of resistance to proteasome inhibition. We focused on Bcl-2, Bcl-x(L) and Mcl-1 as main antiapoptotic factors associated with melanoma progression. Despite an efficient blockage of the proteasome, bortezomib could not counteract the intrinsically high levels of Bcl-2 and Bcl-x(L) in melanoma cells. Moreover, Mcl-1 was only downregulated at late time points after treatment. Based on these results, a combination treatment including (-)-gossypol, an inhibitor of Mcl-1/Bcl-2/Bcl-x(L), was designed and proven effective in vivo. Using a specific RNA interference approach, the survival of bortezomib-treated melanoma cells was found to rely primarily on Mcl-1, and to a lesser extent on Bcl-x(L) (but not on Bcl-2). Importantly, neither Mcl-1 nor Bcl-x(L) inactivation affected the viability of normal melanocytes. This hierarchical requirement of Bcl-2 family members for the maintenance of normal and malignant cells offers a therapeutic window to overcome melanoma chemoresistance in a tumor cell-selective manner.

Li N, Qin H, Li X, Zhou C, Wang D, Ma W, Lin C, Zhang Y, Wang S, Zhang S. · Department of Immunology, Cancer Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100021, China. · J Clin Immunol. · Pubmed #17180470 No free full text.

Abstract: We previously reported that several DNA fragments from human prostate-specific membrane antigen (hPSM), mouse prostatic acid phosphatase (mPAP), and human prostate-specific antigen (hPSA) genes were selected and fused to create a novel hPSM-mPAP-hPSA fusion gene (named 3P gene), and human secondary lymphoid tissue chemokine (SLC), 3P, and human IgG Fc genes were inserted into pcDNA3.1 to construct a DNA vaccine, designated pSLC-3P-Fc. In this report, to establish a more efficient treatment for immunotherapy against prostate cancer, the construct was transfected into B16F10 to generate gene-modified tumor cell vaccine (named B16F10-SLC-3P-Fc). In poorly immunogenic B16F10 mouse melanoma model, the immunization with B16F10-SLC-3P-Fc resulted in a strong antitumor response and 50% of tumor-bearing mice achieved long-term survival (>120 days). In vivo depletion of lymphocytes indicated that CD8(+) T cells were involved in the direct tumor killing, whereas CD4(+) T lymphocytes were required for the induction of CD8(+) CTL response in B16F10-SLC-3P-Fc-immunized mice. Splenocytes from B16F10-SLC-3P-Fc-immunized mice specifically recognized and lysed PSM, PAP, PSA, and 3P expressing tumor cells. The combined therapy of B16F10-SLC-3P-Fc plus anti-B7-H1 MAbs further enhanced the immune response. Rechallenge experiment showed that a persistent memory response was successfully induced by the combined therapy. These observations suggest pSLC-3P-Fc-modified tumor cells could serve as a vaccine against prostate cancer, and the therapy combined with anti-B7-H1 MAbs further enhanced the antitumor immune response.

Verhaegen M, Bauer JA, Martín de la Vega C, Wang G, Wolter KG, Brenner JC, Nikolovska-Coleska Z, Bengtson A, Nair R, Elder JT, Van Brocklin M, Carey TE, Bradford CR, Wang S, Soengas MS. · Department of Dermatology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA. · Cancer Res. · Pubmed #17145881 links to  free full text

Abstract: The RAS/BRAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway is emerging as a key modulator of melanoma initiation and progression. However, a variety of clinical studies indicate that inhibiting the MAPK pathway is insufficient per se to effectively kill melanoma cells. Here, we report on a genetic and pharmacologic approach to identify survival factors responsible for the resistance of melanoma cells to MEK/ERK antagonists. In addition, we describe a new tumor cell-selective means to bypass this resistance in vitro and in vivo. By generating a panel of isogenic cell lines with specific defects in the apoptotic machinery, we found that the ability of melanoma cells to survive in the absence of functional MEK relies on an ERK-independent expression of the antiapoptotic factor Mcl-1 (and to a lesser extent, Bcl-x(L) and Bcl-2). Using computer-based modeling, we developed a novel Bcl-2 homology domain 3 (BH3) mimetic. This compound, named TW-37, is the first rationally designed small molecule with high affinity for Mcl-1, Bcl-x(L), and Bcl-2. Mechanistic analyses of the mode of action of TW-37 showed a synergistic tumor cell killing in the presence of MEK inhibitors. Importantly, TW-37 unveiled an unexpected role of the MAPK pathway in the control of reactive oxygen species (ROS). This function was critical to prevent the activation of proapoptotic functions of p53 in melanoma cells, but surprisingly, it was dispensable for normal melanocytes. Our results suggest that this MAPK-dependent ROS/p53 feedback loop is a point of vulnerability of melanoma cells that can be exploited for rational drug design.

Lin X, Zhou C, Wang S, Wang D, Ma W, Liang X, Lin C, Wang Z, Li J, Guo S, Zhang Y, Zhang S. · Department of Immunology, Cancer Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China. · Int J Cancer. · Pubmed #16708388 No free full text.

Abstract: Human telomerase reverse transcriptase (hTERT) represents an attractive target for cancer immunotherapy because hTERT is reactivated in most human tumors. In an attempt to develop an effective vaccine against most human cancers, we constructed chemotactic-hTERT vaccine. Two hTERT fragments encoding multiple cytotoxic T lymphocyte and T helper cell epitopes were fused as a tumor antigen (named Te). The plasmid based DNA vaccine (pCCL21-Te-Fc) was constructed by linking human CCL21 and IgG Fc gene sequences to each end of Te. In poorly immunogenic B16F10 mouse melanoma model, DNA (pCCL21-Te-Fc) vaccination significantly inhibited tumor growth and all of the mice were dead by day 52. The immunization with pCCL21-Te-Fc-modified tumor cells (B16/CCL21-Te-Fc) resulted in a higher antitumor effect than DNA vaccination and 25% of tumor-bearing mice achieved long-term survival (> 120 days). The combined therapy of B16/CCL21-Te-Fc plus anti-4-1BB MAbs further enhanced the immune response, resulting in 75% of tumor-bearing mice achieved long-term survival (> 120 days) in subcutaneous model and few lung nodules in pulmonary metastasis model. Rechallenge experiment showed that a persistent memory response was successfully induced by the combined therapy. In vivo depletion of lymphocytes indicated that CD8+ T cells were essential in the antitumor activity induced by B16/CCL21-Te-Fc plus anti-4-1BB MAbs, whereas NK cells and CD4+ T cells played substantial roles. The CTL activity induced by pCCL21-Te-Fc-transfected PBMCs specifically lysed a variety of human leukocyte antigen-matched and hTERT-positive human tumor cells, suggesting pCCL21-Te-Fc could serve as a vaccine against most human cancers.

Xu X, Wang S, Chen W, Chen G. · College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400050, China. · J Tradit Chin Med. · Pubmed #16705858 No free full text.

Abstract: OBJECTIVE: To investigate the anti-angiogenesis action of Taohong Siwu Decoction II (THSWD II). METHODS: The chick chorioallantoic membrane (CAM) assay was adopted to study the anti-angiogenesis action of THSWD II; the MTT test was used to investigate its effect on proliferation of the human umbilical vein endothelial cells ECV304; and the immunohistochemical method was used to observe the effect of THSWD II on the expression of kinase insert domain containing receptor/fetal liver kinase 1 (KDR/Flk-1) and the microvessel density (MVD) of B16 melanoma in mice. RESULTS: After treatment with THSWD II, the blood vessel index of CAM and the absorbency of ECV304 in the THSWD II 1 mg/ml group and the 2 mg/ml group decreased significantly (P < 0.01); the weight, the expression of KDR/Flk-1 and the MVD of B16 melanoma in mice reduced significantly in the THSWD II 5 g/kg group, the 10 g/kg group and the TSHSWD 10g/kg plus cyclophosphamide group (P < 0.01). CONCLUSION: THSWD II has the actions of anti-angiogenesis, and inhibiting the proliferation of ECV304 cells and the growth of B16 melanoma. The clinical anti-tumour mechanism is considered to berelated possibly to its anti-angiogenesis action by inhibiting the expression of KDR/FIK-1.

Che XC, Lu R, Hu JX, Zheng MN, Zhang MF, Wang S, Yu CY, Yang XL, Xing DH, Yao Z. · Department of Immunology, Tianjin Medical University, Tianjin 300070, P. R. China. · Ai Zheng. · Pubmed #16536978 No free full text.

Abstract: BACKGROUND & OBJECTIVE: Tripeptide compound tyroservaltide (YSV) has obvious inhibitory effect on experimental liver cancer. This study was to evaluate the inhibitory effect of YSV on the invasion and metastasis of mouse melanoma cell line B16-F10. METHODS: The cytotoxic effect of YSV on B16-F10 cells was assessed by MTT assay, and the effects of YSV on the adhesiveness and invasiveness of B16-F10 cells were determined using Matrigel and a transwell system. B16-F10 cells were injected into the tail veins of C57BL/6 mice to establish an experimental lung metastasis model, and the effect of YSV on lung metastasis was observed. The effect of YSV on the expression of intercellular adhesion molecule-1 (ICAM-1) in lung tissue was detected by immunohistochemistry. RESULTS: YSV (100 microg/ml, 48 h) inhibited the proliferation of B16-F10 cells, with an inhibitory rate of 24.36%; YSV (100 microg/ml, 24 h) inhibited the adhesiveness of B16-F10 cells to Matrigel, with an inhibitory rate of 36.51%; YSV (10 microg/ml, 48 h) inhibited the invasiveness of B16-F10 cells, with an inhibitory rate of 36.53%; YSV [640 microg.(kg.d)-1] inhibited lung metastasis by B16-F10 cells, with an inhibitory rate of 62.21%. The expression of ICAM-1 in lung tissue was lower in YSV group than in normal saline group. CONCLUSION: YSV can inhibit the growth, invasion, and metastasis of B16-F10 cells.

Wang S, Coleman EJ, Pop LM, Brooks KJ, Vitetta ES, Niederkorn JY. · Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College of HUST, Wuhan, PR China. · Int J Cancer. · Pubmed #16152588 No free full text.

Abstract: We have shown that administration of a novel anti-CD54 monoclonal antibody (UV3) results in long-term survival of SCID mice bearing human myeloma xenografts. Previous studies have demonstrated a link between the expression of CD54 and the progression of uveal melanoma. Our study assessed the expression of CD54 on 7 human uveal melanoma cell lines and 3 cell lines established from uveal melanoma metastases. In vivo studies examined the efficacy of systemic and local administration of UV3 antibody on the progression of uveal melanoma cells transplanted either heterotopically or orthotopically into SCID mice. Five of the 7 primary uveal melanoma cell lines and all 3 of the metastases cell lines expressed CD54. Intraperitoneal injection of either IgG or F(ab')2 fragments of UV3 significantly inhibited the growth of subcutaneous and intraocular melanomas. Subconjunctival injection of either IgG or F(ab')2 fragments of UV3 produced a significant reduction in the growth of intraocular melanomas, even if the antibody was administered after the appearance of intraocular tumors. The results indicate that both primary and metastatic human uveal melanoma cells express CD54. The marked inhibition of intraocular and subcutaneous uveal melanoma progression suggests that UV3 antibody is a promising therapeutic agent for further evaluation in patients with uveal melanoma. This is especially noteworthy, as no existing therapeutic modality prevents metastasis of uveal melanoma or prolongs the survival of patients with uveal melanoma.

Wang S, Robertson GP, Zhu J. · Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA. · Gene. · Pubmed #15563832 No free full text.

Abstract: Polycomb group (PcG) proteins function to maintain the stable epigenetic repression of homeotic genes and other important developmental and cell cycle regulatory genes. Such maintenance establishes a form of cellular memory for its identity or state of differentiation. Accumulating evidence indicates that perturbation of this transcriptional memory may be required for tumor progression and may represent a hallmark of cancer. We have identified a novel gene encoding a human homologue of the Drosophila polycomblike protein, hPCL3. Through alternative polyadenylation and/or splicing, the gene encodes two nuclear proteins, hPCL3S and hPCL3L. Both proteins repressed transcription upon recruitment to the proximity of an HSV-tk promoter by a Gal4 DNA binding domain. Interestingly, the products of the hPCL3 gene, particularly the short form, hPCL3S, are markedly overexpressed in many types of cancers, including colon, skin, lung, rectal, cervical, uterus, and liver cancers. This increase in expression correlated with tumor progression. Both hPCL3S and hPCL3L messages were increased dramatically in most cell lines derived from various stages of melanoma and glioma tumor progression. Thus, our data link PcG deregulation to the progression of multiple cancers and may have important implications for unraveling the mechanisms of tumor progression.

Li S, Wang S. · Department of Pathology, Affiliated Eye Ear Nose Throat Hospital of Fudan University, Shanghai, 200031, China. · Lin Chuang Er Bi Yan Hou Ke Za Zhi. · Pubmed #15311506 No free full text.

Abstract: OBJECTIVE: To study the clinicopathological features of otolaryngol melanoma and to elucidate its diagnosis. METHOD: The clinical data were reviewed retrospectively and immunohistochemical stains were performed in 40 cases of melanoma. RESULT: The course of the disease was aggressive. Three histological types were found: big epithelioid cell type (25 cases), small lymphoid cell type (12 cases) and spindle cell type (3 cases). The tumor cells were positive for VIM, S-100, HMB45. CONCLUSION: Otolaryngol melanoma is a rare tumor. It can be differentiated from other head and neck tumors based on the histopathologic features and immunohistochemical finds. Histological type of the tumor is important for clinical therapy and prognostic evaluation.

Li Y, Wang S, Zhao JZ. · Department of Neurosurgery, Beijing Tiantan Hospital, Beijing 100050, China. · Zhonghua Yi Xue Za Zhi. · Pubmed #14990130 No free full text.

Abstract: OBJECTIVE: To investigate the diagnosis and treatment of melanomas of the central nervous system. METHODS: The clinical data, including presentation, treatment, operative finding, histological diagnosis and prognosis of 15 patients with melanomas of central nervous system who underwent surgery 1996 - 2003 were reviewed. RESULTS: There were 12 cases of intracranial melanoma and 3 cases of spinal cord melanomas. No distinctive symptoms occurred in these patients. Total resection was achieved in 5 cases, and subtotal resection in 10 cases. Histological examination showed melanoma in 10 cases, meningeal melanocytoma in 4 cases, and amelanotic melanoma in 1 case. Ten cases were followed up for 3 months to 9 years. Among the 10 cases only 1 survived. CONCLUSION: Melanoma of the central nervous system is an extremely rare tumor and difficult to get correct preoperative diagnosis. Microsurgery combined with radiotherapy or gamma-knife therapy is recommended. The prognosis is very poor.

Rosenwald IB, Wang S, Savas L, Woda B, Pullman J. · Department of Pathology, Montefiore Medical Center, Bronx, New York, USA. · Cancer. · Pubmed #12942578 links to  free full text

Abstract: BACKGROUND: Stimulation of resting cells by growth factors leads to an increase in the rate of protein synthesis, which is necessary for cell growth and division. Translation initiation factor eIF-2alpha is one of the key translation factors mediating the effects of growth factors on protein synthesis. In normal cells, expression of eIF-2alpha is increased transiently, but its levels are elevated constitutively in oncogene-transformed cells. Overexpression of constitutively active eIF-2alpha in rodent cells makes them tumorigenic. In this article, the authors report their findings on the increased expression of eIF-2alpha in human benign and malignant neoplasms originating from melanocytes and colonic epithelium. METHODS: Immunohistochemistry was used to analyze the expression of eIF-2alpha, eIF-4E, and cyclin D1 in melanocytic nevi and melanomas and the expression of eIF-2alpha in colonic adenomas and carcinomas. RESULTS: The authors found that the expression of eIF-2alpha was increased markedly in both benign and malignant neoplasms of melanocytes and colonic epithelium. CONCLUSIONS: Increased expression of eIF-2alpha took place in both benign and malignant neoplasms of melanocytes and colonic epithelium. These findings suggest that elevated expression of this translation initiation factor may contribute to tumor initiation and progression but that it is not sufficient for establishing a malignant phenotype in the tumors analyzed in this study.

Wu Y, Yi C, Wang S, Zhang M, Zhang J. · Department of Pathophysiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, China. · Sichuan Da Xue Xue Bao Yi Xue Ban. · Pubmed #12910682 No free full text.

Abstract: OBJECTIVE: To investigate the tumor-targeting of bifidobacterium infantis to melanoma. METHODS: After bolus administration of bifidobacterium infantis with 3H-TdR tagged, the values of radioactivity in tumor and organs were examined at days 1, 2, 3, 4 and 7. Anaerobic culture and histological observation of tumor and normal organs were taken for the examination of tumor-targeting characteristics of bifidobacterium infantis. RESULTS: The radioactivity in melanoma tissue increased progressively, while the radioactivity in normal organs became attenuated with time. The anaerobic culture showed an obvious proliferation of bifidobacterium infantis in tumor tissue. A large part of area was Gram positive in the tumor tissue section, whereas the normal tissue was Gram negative. CONCLUSION: Bifidobacterium infantis has good tumor-targeting characteristics in mice melanoma.

Wang S, Stewart JM, Ross MI, Prieto VG. · Department of Pathology, The University of Texas M. D. Anderson Cancer Center, 77030, USA. · Ann Diagn Pathol. · Pubmed #12715334 No free full text.

Abstract: A 51-year-old male presented with a 5 cm left knee mass. Fine needle aspiration revealed large epithelioid cells with prominent nucleoli and abundant cytoplasmic pigment, consistent with malignant melanoma. Left inguinal lymphadenopathy was present, which was suspicious for metastatic disease by ultrasound examination. A dark perianal skin lesion was also identified, therefore raising the possibility of a primary melanoma. The knee and perianal lesions were resected and inguinal sentinel node biopsy was performed. In the specimen from the knee, there were clusters and fascicles of spindle and epithelioid cells with prominent nucleoli. Many of the cells displayed abundant, granular, brown, cytoplasmic pigment. The lymph node showed clusters of similar cells located in the subcapsular sinus. Immunohistochemical study showed that the cells expressed CD68, but failed to express S-100, MART-1, and gp100. The cytoplasmic pigment was positive for iron staining. The final diagnosis was pigmented villonodular synovitis. This case illustrates that pigmented villonodular synovitis may present with lymphadenopathy, mimicking a malignant process, including melanoma. Immunohistochemical studies may be essential for establishing the correct diagnosis.

Wang S, Qi J, Smith M, Link CJ. · Human Gene Therapy Research Institute, Iowa Methodist Medical Center, Des Moines 50309, USA. · Cancer Gene Ther. · Pubmed #11916238 links to  free full text

Abstract: Herpes simplex virus type-1 (HSV-1) has been demonstrated as a potentially useful gene delivery vector for gene therapy due to its high efficiency of in vivo transduction. The helper virus-dependent, HSV- 1 amplicon vectors were developed for easier operation and their larger capacity. In this study, the herpes simplex virus type-1 thymidine kinase (HSVtk) gene was cloned into the pHE700 amplicon vector to make an HE7tk vector and used for in vivo gene delivery. Human melanoma xenografts were established in athymic nude mice. Tumors were injected directly with HE7tk vector alone, HE7tk vector followed by ganciclovir (GCV), or a pHE700 amplicon vector carrying a green fluorescent protein (HE7GFP) gene followed by GCV. Efficient HSVtk transgene expression was found in the tumor 3 days after injection. Animals transduced with HE7tk followed by GCV had minimal tumor growth (P < .01 ). Animals that received either HE7tk vector without GCV or HE7GFP vector with GCV had some reduction in tumor growth compared to animals that were injected with buffer only. These data indicate that replication-defective HSV-1 amplicon vectors can be used effectively to deliver transgenes into solid tumors in vivo.

Yang H, Wang S, Liu Z, Wu MH, McAlpine B, Ansel J, Armstrong C, Wu G. · Departments of Microbiology and Immunology, Emory University School of Medicine, GA 30322, Atlanta, USA. · Gene. · Pubmed #11255016 No free full text.

Abstract: The cell surface adhesion molecule human MUC18 (huMUC18 or Mel-CAM) has been postulated to play a key pathogenic role in metastatic melanoma progression. To establish an immunocompetent syngeneic mouse model that would greatly facilitate our understanding of the role of MUC18 in the metastatic behavior of melanoma, we cloned and characterized the mouse MUC18 (muMUC18) cDNA gene. The gene was amplified by RT-PCR and RACE of the poly(A)+RNA isolated from the mouse melanoma cell line B16F10/Queens. The cloned muMUC18 cDNA gene contained 28 nucleotides of 5'-UTR, 908 nucleotides of 3'-UTR, and an open reading frame (ORF) of 1947 nucleotides encoding a protein of 648 amino acids, which is two amino acids longer than huMUC18. The size of the muMUC18 mRNA is about 3 kb with a shorter 3'-UTR than the huMUC18 mRNA (about 3.3 kb). Besides, the sequence in the 3' UTR of the two mRNAs is diverse with only 31% identity. The 5'-UTR and coding sequences of the muMUC18 cDNA are 72.4 and 80.6% identical to those of huMUC18, respectively. The deduced amino acid sequence of the muMUC18 cDNA is 76.2% identical to that of huMUC18. The amino acid sequences deduced from MUC18 cDNA sequences from six other mouse melanoma cell lines are identical except one to three residues, suggesting that the muMUC18 cDNA sequence determined in this report is correct. The muMUC18 protein is predicted to be slightly more acidic than the human protein. The levels of muMUC18 mRNA and protein in nine mouse melanoma cell lines were directly proportional to their ability to establish metastatic colonies in lungs of syngeneic mice. Most biological functions of the muMUC18 may be similar to the huMUC18.