儘管歷年來在開發新型標靶藥物上有了不少進展，轉移性癌症仍舊佔了全球多數的癌症死亡率之首，並且對現今的治療方式有著強烈的抵抗性。癌症轉移(Metastasis)的生成是藉由血管新生，細胞外滲，躲避免疫監視，附著及在不同器官中複製擴張等多重步驟所組成的現象。若想有效的控制癌轉移則需要能進行全身性(systemic)的療法。過去的研究指出：具有促進發炎及細胞存活等特性nuclear factor kappa B (NFκB)因子，在腫瘤細胞中的癌轉移過程扮演著重要的作用，並被公認為一個在控制癌轉移上極好的標靶。前-腦啡-黑色素激素-腎上腺皮質激素 (pro-opiomelanocortin, POMC) 與其所衍生出來的腎上腺皮質激素 (ACTH)，α-, β-, and γ-黑色素激素(α-, β-, and γ-MSH)，β-腦內啡(β-EP)等眾多神經胜肽均具有能顯著抑制NFκB途徑的功能。除了調控壓力反應及體內能量平衡之外，POMC亦具有調節皮膚色素、發炎反應，及周邊系統免疫等作用。我們最近的研究發現，在周邊利用腺病毒作為載體來表現POMC基因能提升血液循環以及肝臟中POMC蛋白質的表現量，並且能有效的抑制B16F10惡性黑色素瘤(melanoma)生長及延長帶有腫瘤老鼠的生命。更進一步的，我們發現同時使用POMC與順鉑(cisplatin)的治療能提高POMC的延命療效。經由分析後，我們發現POMC能抑制惡性黑色素瘤中NFκB的活性，並且造成黑色素癌細胞凋亡，重新分化及抗血管新生等。此外，我們還發現POMC基因可透過抑制黑色素細胞的「上皮細胞間質轉型」(Epithelial-mesenchymal transition; EMT：即從上皮細胞型態(epithelium)轉變成間葉細胞(mesenchyme)型態的一種特殊過程)。我們也發現POMC抑制黑色素癌細胞生長可能會透過α-MSH與黑皮質素受器-1 (Melanocortin-1 receptor; MC1R)作用的機轉。
為了探討POMC在其他種類癌症上的應用，我們利用一株不具有MC1R表現的Lewis lung carcinoma (LLC)細胞作為研究標的。我們也發現，POMC基因表現不但可以有效抑制LLC細胞在體外培養狀態下的生長，POMC也可有效地抑制LLC腫瘤在老鼠上的生長。利用組織學的研究也發現POMC基因傳送可有效抑制LLC腫瘤的細胞增生、促進LLC細胞凋亡、並阻斷腫瘤周邊的血管新生。此外，POMC基因傳送會抑制β-catenin的活性及其下游之原致癌基因(proto-oncogenes)，如cyclin D1及c-myc的蛋白質表現。這些結果也更進一步證實儘管POMC在沒有MC1R的表現之下，仍可有效的抑制癌症生長，我們也確認POMC可以用來治療不只一種癌症。
由於POMC及其衍生胜肽已知具有免疫調控的作用，為了探討POMC的抗癌機制與宿主免疫系統之間的關聯，我們利用免疫缺現(SCID)與正常老鼠(C57BL/6)的黑色素癌模式比較之下，POMC基因治療在這兩者之間皆可有效抑制腫瘤生長。然而，我們也發現POMC基因傳送會造成正常老鼠的脾臟萎縮且會減少周邊淋巴球的數目。研究結果顯示POMC的抗癌機制可能與宿主的免疫系統是否正常無關，但也可發現POMC的免疫抑制可能與ACTH/cortisol的生成有極大關聯。為了減少POMC基因治療所造成的副作用，我們合成了一系列帶有不同ACTH區域突變的POMC基因；如在POMC的ACTH第15個及第17個胺基酸位置坐點突變；ACTH(K15/R17A)。相較於POMC原始基因，ACTH(K15/R17A)基因可減少ACTH表現量且可減緩corticosterone在細胞內以及動物體內的合成。此外，ACTH(K15/R17A)基因表現不僅可抑制原位的黑色素癌生長，亦可有效控制轉移性黑色素癌的生成且不具有任何免疫抑制的副作用。總結以上的研究，我們已更詳盡地得知POMC基因對於抑癌的功能及機轉。更甚者，我們也進一步去改善POMC基因治療的副作用已做為未來在癌症治療上的應用。

Despite the development of novel target therapy drugs in recent years, metastatic cancer remains refractory to current cancer therapies and accounts for the majority of cancer mortalities worldwide. Metastasis consists of multiple steps including angiogenesis, extravasion, escape from immune surveillance, adhesion, and clonal expansion in different organs that a systemic therapy is required for effective control of metastasis. The pro-inflammatory nuclear factor kappa B (NFκB) pathway plays an important role during each of these metastatic events and constitutes an excellent target for metastasis control. Stress hormone pro-opiomelanocortin (POMC) and its derived neuropeptides including corticotrophin (ACTH), α-, β-, and γ-melanocyte–stimulating hormone (α-, β-, and γ-MSH), β-endorphin are potent inhibitors of NFκB pathway. Other than the central regulation of stress response and energy homeostasis, POMC also regulates the skin pigmentation, inflammatory processes, and immune reactions in the peripheral system. Since adenovirus–mediated POMC gene delivery leads to hepatic POMC expression, it seems plausible that POMC gene therapy may elicit systemic production of anti-inflammatory POMC-derived peptides and hold promises for control of primary and metastatic cancers. In B16-F10 melanoma models, POMC gene delivery elevated the circulating ACTH levels for more than 8 weeks and suppressed the growth of established melanoma, thereby prolonging the life span of tumor-bearing mice. Moreover, combination of POMC therapy with cisplatin further enhances the survival outcome. Subsequent analysis reveals that POMC gene therapy inhibits the growth and metastasis of melanoma through apoptosis, angiogenesis inhibition, and modulation of epithelial-mesenchymal transition. Besides, α-MSH/melanortin-1 receptor (MC-1R) pathway is involved in the POMC-mediated melanoma suppression.
To investigate whether POMC therapy could be applied to other types of tumor, we evaluated the therapeutic efficacy of POMC gene therapy in Lewis lung carcinoma (LLC) cells which lack MC-1R. Interestingly, POMC gene delivery effectively inhibited the proliferation and colony formation of LLC cells in vitro and the growth of established LLC in mice. Histological analysis indicated that POMC gene delivery attenuated LLC through proliferation inhibition, apoptosis induction, and angiogenesis blockade. Moreover, POMC gene delivery perturbed β-catenin signaling by reducing protein levels of β-catenin and its downstream proto-oncogenes, including cyclin D1 and c-myc. These results support the existence of an MC-1R-independent pathway for POMC gene therapy and expand the therapeutic spectrum of POMC therapy for multiple types of cancer.
To elucidate the role of host immunity in anti-neoplastic mechanism underlying POMC therapy, we compared the treatment efficacy of POMC gene therapy for B16-F10 melanoma between severe combined immune-deficient (SCID) and immune-competent C57BL/6 mice, and found similar extent of tumor suppression in both strains of mice. In addition, POMC gene therapy reduced the spleen weight and the number of circulating lymphocytes in B6 mice. These findings suggest that POMC therapy was not dependent on host immunity, yet instead induced immune suppression of animals through ACTH/cortisol production. To minimize such side effect of POMC therapy, we generated a series of adenovirus vectors encoding POMC with mutations in ACTH domain (ACTH-K15A/R17A), which fails to stimulate cortisol synthesis in vitro and in vivo. Gene delivery of ACTH (K15A/R17A) remained capable of suppressing the primary and metastatic melanoma, but had no effect on immune functions in mice. In conclusion, we have characterized the anti-neoplastic function and mechanism of POMC therapy for cancer. Furthermore, we have developed improved POMC gene vectors to minimize its adverse effect for future cancer therapy.

Abstract in Chinese I
Abstract in English III
Index VI
Figure Index XI Index XV
Abbreviations XVI

Contents 1
Chapter 1. General Introducion .1
1.1 Proopiomelanocortin (POMC) 2
1.2 Melanocortin receptors (MCRs) 4
1.3 Melanoma and metastasis 7
1.4 Melanoma an animal models 10
1.5 POMC and Melanoma 11
1.6 Specific Aims 13
Chapter 2. The Anti-metastatic Potential of POMC Gene Transfer in Melanoma .14
2.1 Introduction 15
2.2 Materials and Methods .17
2.3 Results 20
Adenovirus-mediated POMC overexpression in B16-F10 melanoma cells 20
POMC gene delivery potently inhibited the lung metastasis of melanoma in vivo 20
POMC gene delivery inhibited the neovascularization and colonization of B16-F10 cells in lung 21
2.4 Discussions .23
2.5 Figures and Legends 25
Chapter 3. The underlying mechanism of POMC-mediated metastatic melanoma inhibition .30
3.1 Introduction 31
3.2 Materials and Methods 34
3.3 Results 40
POMC gene delivery effectively attenuated the motility ability and the invasive capability of melanoma cells in vitro 41
POMC gene delivery inhibited the expression of Rho family proteins in B16-F10 melanoma cells and metastatic foci .41
POMC gene delivery reversed epithelial-mesenchymal transition of melanoma through up-regulation of E-cadherin and down-regulation of vimentin and α-SMA 42
POMC gene delivery elicited HDGF downregulation in B16-F10 cells and metastatic melanoma 42
Exogenous HDGF supply partially attenuated the POMC-induced invasiveness suppression and EMT change in melanoma cells 43
Mimicking POMC gene delivery by POMC-derived peptides induces feature on inhibition of invasion and reduced EMT change in melanoma cells 44
3.4 Discussions 45
3.5 Figures and Legends .49
Chapter 4. Role of Melanocortin Receptor-1 (MC1R) expression in POMC-mediated Tumor Suppression 59
4.1 Abstract 60
4.2 Introduction 61
4.3 Materials and Methods 63
4.4 Results 70
Defective MC-1R expression and signaling in mouse LLC cells .70
POMC gene delivery inhibited the malignant behaviors in LLC cells .70
Systemic POMC gene delivery attenuates tumor growth in mice bearing established LLC 71
Systemic POMC gene delivery attenuates tumor progression and inhibits β-catenin pathway in tumor tissue of LLC 72
Systemic POMC gene delivery inhibits blood vessel formation in LLC tumor tissue 73
4.5 Discussions 74
4.6 Figures and Legends 77
Chapter 5. Role of host immunity in POMC over-expresssion in vivo 89
5.1 Introduction 90
5.2 Materials and Methods .93
5.3 Results 96
Systemic POMC expression elevated plasma ACTH level in C57BL/6 mice...96
Systemic POMC expression caused depletion of host immune system in C57BL/6 mice .96
Systemic POMC expression caused depletion of splenocytes in C57BL/6 mice 96
Systemic of POMC expression is caused depletion of peripherial lymphocytes in C57BL/6 mice 97
Host immunity is not required for of POMC induced tumor suppression in melanoma 98
5.4 Discussions 99
5.5 Figures and Legends 102
Chapter 6. Generate a POMC mutant to diminish the side-effect of POMC gene therapy in vitro and in vivo 109
6.1 Introduction 110
6.2 Materials and Methods 115
6.3 Results 120
Adenovirus effectively transduced POMC and ACTH (K15A/R17A) expression in B16-F10 cells 120
ACTH (K15A/R17A) gene delivery preserved the anti-invasive and anti-tumor potential of POMC in melanoma cells .121
ACTH (K15A/R17A) gene delivery does not induced the steroidogenic activity in C57BL/6 mice. 121
ACTH (K15A/R17A) gene delivery reduced POMC-mediated immune suppression in C57BL/6 mice. 122
Systemic ACTH (K15A/R17A) expression attenuated the growth of established melanoma and metastatic melanoma in C57BL/6 mice 123
6.4 Discussions 125
6.5 Figures and Legends 129
General Conclusions .139
Appendix 145
References 157
Publications 171
Conference Presentations 173
Publication Manuscripts 175

Abdel-Malek, Z.A., 2011. Development of alpha-Melanocortin Analogs for Melanoma Prevention and Targeting. Adv Exp Med Biol 681, 126-132.
Abe, H., Kamai, T., Tsujii, T., Nakamura, F., Mashidori, T., Mizuno, T., Tanaka, M., Tatsumiya, K., Furuya, N., Masuda, A., Yamanishi, T., Yoshida, K., 2008. Possible role of the RhoC/ROCK pathway in progression of clear cell renal cell carcinoma. Biomed Res 29, 155-161.
Amiri, K.I., Richmond, A., 2005. Role of nuclear factor-kappa B in melanoma. Cancer Metastasis Rev 24, 301-313.
Arenberg, D.A., Keane, M.P., DiGiovine, B., Kunkel, S.L., Strom, S.R., Burdick, M.D., Iannettoni, M.D., Strieter, R.M., 2000. Macrophage infiltration in human non-small-cell lung cancer: the role of CC chemokines. Cancer Immunol Immunother 49, 63-70.
Averbook, B.J., Wei, J.P., Perry-Lalley, D.M., Rosenberg, S.A., Yang, J.C., 1993. A tumor-elaborated supernatant factor chemotactic for IL-2 expanded tumor infiltrating T-lymphocytes. Lymphokine Cytokine Res 12, 1-8.
Avraamides, C.J., Garmy-Susini, B., Varner, J.A., 2008. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8, 604-617.
Bar-Eli, M., 1997. Molecular mechanisms of melanoma metastasis. J Cell Physiol 173, 275-278.
Barnes, P.J., 2006. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 148, 245-254.
Bateman, A., Singh, A., Kral, T., Solomon, S., 1989. The immune-hypothalamic-pituitary-adrenal axis. Endocr Rev 10, 92-112.
Baum, B., Settleman, J., Quinlan, M.P., 2008. Transitions between epithelial and mesenchymal states in development and disease. Semin Cell Dev Biol 19, 294-308.
Becher, E., Mahnke, K., Brzoska, T., Kalden, D.H., Grabbe, S., Luger, T.A., 1999. Human peripheral blood-derived dendritic cells express functional melanocortin receptor MC-1R. Ann N Y Acad Sci 885, 188-195.
Berg, D., Otley, C.C., 2002. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management. J Am Acad Dermatol 47, 1-17; quiz 18-20.
Bernard, K., Litman, E., Fitzpatrick, J.L., Shellman, Y.G., Argast, G., Polvinen, K., Everett, A.D., Fukasawa, K., Norris, D.A., Ahn, N.G., Resing, K.A., 2003. Functional proteomic analysis of melanoma progression. Cancer Res 63, 6716-6725.
Bhardwaj, R., Becher, E., Mahnke, K., Hartmeyer, M., Schwarz, T., Scholzen, T., Luger, T.A., 1997. Evidence for the differential expression of the functional alpha-melanocyte-stimulating hormone receptor MC-1 on human monocytes. J Immunol 158, 3378-3384.
Bhatia, S., Thompson, J.A., 2012. Systemic therapy for metastatic melanoma in 2012: dawn of a new era. J Natl Compr Canc Netw 10, 403-412.
Bicknell, A.B., 2008. The tissue-specific processing of pro-opiomelanocortin. J Neuroendocrinol 20, 692-699.
Blalock, J.E., 1985. Proopiomelanocortin-derived peptides in the immune system. Clin Endocrinol (Oxf) 22, 823-827.
Blalock, J.E., 1999. Proopiomelanocortin and the immune-neuroendocrine connection. Ann N Y Acad Sci 885, 161-172.
Blalock, J.E., Smith, E.M., 1980. Human leukocyte interferon: structural and biological relatedness to adrenocorticotropic hormone and endorphins. Proc Natl Acad Sci U S A 77, 5972-5974.
Bohm, M., Wolff, I., Scholzen, T.E., Robinson, S.J., Healy, E., Luger, T.A., Schwarz, T., Schwarz, A., 2005. alpha-Melanocyte-stimulating hormone protects from ultraviolet radiation-induced apoptosis and DNA damage. J Biol Chem 280, 5795-5802.
Bonitsis, N., Batistatou, A., Karantima, S., Charalabopoulos, K., 2006. The role of cadherin/catenin complex in malignant melanoma. Exp Oncol 28, 187-193.
Bregman, M.D., Abdel Malek, Z.A., Meyskens, F.L., Jr., 1985. Anchorage-independent growth of murine melanoma in serum-less media is dependent on insulin or melanocyte-stimulating hormone. Exp Cell Res 157, 419-428.
Butler, A.A., Kesterson, R.A., Khong, K., Cullen, M.J., Pelleymounter, M.A., Dekoning, J., Baetscher, M., Cone, R.D., 2000. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141, 3518-3521.
Catania, A., 2007. The melanocortin system in leukocyte biology. J Leukoc Biol 81, 383-392.
Catania, A., Delgado, R., Airaghi, L., Cutuli, M., Garofalo, L., Carlin, A., Demitri, M.T., Lipton, J.M., 1999. alpha-MSH in systemic inflammation. Central and peripheral actions. Ann N Y Acad Sci 885, 183-187.
Catania, A., Gatti, S., Colombo, G., Lipton, J.M., 2004. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol Rev 56, 1-29.
Catania, A., Lipton, J.M., 1993a. Alpha-melanocyte-stimulating hormone peptides in host responses. From basic evidence to human research. Ann N Y Acad Sci 680, 412-423.
Catania, A., Lipton, J.M., 1993b. alpha-Melanocyte stimulating hormone in the modulation of host reactions. Endocr Rev 14, 564-576.
Cebon, J., Gedye, C., John, T., Davis, I.D., 2007. Immunotherapy of advanced or metastatic melanoma. Clin Adv Hematol Oncol 5, 994-1006.
Chambers, A.F., Groom, A.C., MacDonald, I.C., 2002. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2, 563-572.
Chen, A.S., Marsh, D.J., Trumbauer, M.E., Frazier, E.G., Guan, X.M., Yu, H., Rosenblum, C.I., Vongs, A., Feng, Y., Cao, L., Metzger, J.M., Strack, A.M., Camacho, R.E., Mellin, T.N., Nunes, C.N., Min, W., Fisher, J., Gopal-Truter, S., MacIntyre, D.E., Chen, H.Y., Van der Ploeg, L.H., 2000. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 26, 97-102.
Chen, S.C., Kung, M.L., Hu, T.H., Chen, H.Y., Wu, J.C., Kuo, H.M., Tsai, H.E., Lin, Y.W., Wen, Z.H., Liu, J.K., Yeh, M.H., Tai, M.H., 2012. Hepatoma-Derived Growth Factor Regulates breast cancer cell invasion by Modulating Epithelial Mesenchymal Transition. J Pathol.
Chen, W., Kelly, M.A., Opitz-Araya, X., Thomas, R.E., Low, M.J., Cone, R.D., 1997. Exocrine gland dysfunction in MC5-R-deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell 91, 789-798.
Chida, D., Nakagawa, S., Nagai, S., Sagara, H., Katsumata, H., Imaki, T., Suzuki, H., Mitani, F., Ogishima, T., Shimizu, C., Kotaki, H., Kakuta, S., Sudo, K., Koike, T., Kubo, M., Iwakura, Y., 2007. Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis. Proc Natl Acad Sci U S A 104, 18205-18210.
Chretien, M., Benjannet, S., Gossard, F., Gianoulakis, C., Crine, P., Lis, M., Seidah, N.G., 1979. From beta-lipotropin to beta-endorphin and 'pro-opio-melanocortin'. Can J Biochem 57, 1111-1121.
Clark, E.A., Golub, T.R., Lander, E.S., Hynes, R.O., 2000. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532-535.
Clark, W.H., Jr., Elder, D.E., Guerry, D.t., Braitman, L.E., Trock, B.J., Schultz, D., Synnestvedt, M., Halpern, A.C., 1989. Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 81, 1893-1904.
Coll, A.P., Farooqi, I.S., Challis, B.G., Yeo, G.S., O'Rahilly, S., 2004. Proopiomelanocortin and energy balance: insights from human and murine genetics. J Clin Endocrinol Metab 89, 2557-2562.
Cone, R.D., 1999. The Central Melanocortin System and Energy Homeostasis. Trends Endocrinol Metab 10, 211-216.
Connell, J.M., Davies, E., 2005. The new biology of aldosterone. J Endocrinol 186, 1-20.
Cooke, B.A., 1999. Signal transduction involving cyclic AMP-dependent and cyclic AMP-independent mechanisms in the control of steroidogenesis. Mol Cell Endocrinol 151, 25-35.
Cooper, A., Robinson, S.J., Pickard, C., Jackson, C.L., Friedmann, P.S., Healy, E., 2005. Alpha-melanocyte-stimulating hormone suppresses antigen-induced lymphocyte proliferation in humans independently of melanocortin 1 receptor gene status. J Immunol 175, 4806-4813.
Costa, J.L., Bui, S., Reed, P., Dores, R.M., Brennan, M.B., Hochgeschwender, U., 2004. Mutational analysis of evolutionarily conserved ACTH residues. Gen Comp Endocrinol 136, 12-16.
Cozza, E.N., Vila, M.C., Acevedo-Duncan, M., Farese, R.V., Gomez-Sanchez, C.E., 1990. Treatment of primary cultures of calf adrenal glomerulosa cells with adrenocorticotropin (ACTH) and phorbol esters: a comparative study of the effects on aldosterone production and ACTH signaling system. Endocrinology 126, 2169-2176.
Crosby, T., Fish, R., Coles, B., Mason, M.D., 2000. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev, CD001215.
Dinh, Q.Q., Chong, A.H., 2007. Melanoma in organ transplant recipients: the old enemy finds a new battleground. Australas J Dermatol 48, 199-207.
Dolcet, X., Llobet, D., Pallares, J., Matias-Guiu, X., 2005. NF-kB in development and progression of human cancer. Virchows Arch 446, 475-482.
Dores, R.M., Lecaude, S., 2005. Trends in the evolution of the proopiomelanocortin gene. Gen Comp Endocrinol 142, 81-93.
Dorr, R.T., Lines, R., Levine, N., Brooks, C., Xiang, L., Hruby, V.J., Hadley, M.E., 1996. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci 58, 1777-1784.
Dunn, G.P., Bruce, A.T., Ikeda, H., Old, L.J., Schreiber, R.D., 2002. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3, 991-998.
Dunn, G.P., Koebel, C.M., Schreiber, R.D., 2006. Interferons, immunity and cancer immunoediting. Nat Rev Immunol 6, 836-848.
Eigentler, T.K., Garbe, C., 2006. Malignant melanoma: classification and staging of malignant melanoma. Front Radiat Ther Oncol 39, 149-158.
Ellenbroek, S.I., Collard, J.G., 2007. Rho GTPases: functions and association with cancer. Clin Exp Metastasis 24, 657-672.
Everett, A.D., Narron, J.V., Stoops, T., Nakamura, H., Tucker, A., 2004. Hepatoma-derived growth factor is a pulmonary endothelial cell-expressed angiogenic factor. Am J Physiol Lung Cell Mol Physiol 286, L1194-1201.
Everett, A.D., Stoops, T., McNamara, C.A., 2001. Nuclear targeting is required for hepatoma-derived growth factor-stimulated mitogenesis in vascular smooth muscle cells. J Biol Chem 276, 37564-37568.
Everett, A.D., Yang, J., Rahman, M., Dulloor, P., Brautigan, D.L., 2011. Mitotic phosphorylation activates hepatoma-derived growth factor as a mitogen. BMC Cell Biol 12, 15.
Eves, P., Haycock, J., Layton, C., Wagner, M., Kemp, H., Szabo, M., Morandini, R., Ghanem, G., Garcia-Borron, J.C., Jimenez-Cervantes, C., Mac Neil, S., 2003. Anti-inflammatory and anti-invasive effects of alpha-melanocyte-stimulating hormone in human melanoma cells. Br J Cancer 89, 2004-2015.
Eves, P.C., Macneil, S., Haycock, J.W., 2005. alpha-Melanocyte stimulating hormone, inflammation and human melanoma. Peptides.
Fargnoli, M.C., Gandini, S., Peris, K., Maisonneuve, P., Raimondi, S., 2010. MC1R variants increase melanoma risk in families with CDKN2A mutations: a meta-analysis. Eur J Cancer 46, 1413-1420.
Ferradini, L., Mackensen, A., Genevee, C., Bosq, J., Duvillard, P., Avril, M.F., Hercend, T., 1993. Analysis of T cell receptor variability in tumor-infiltrating lymphocytes from a human regressive melanoma. Evidence for in situ T cell clonal expansion. J Clin Invest 91, 1183-1190.
Fitzsimons, H.L., Bland, R.J., During, M.J., 2002. Promoters and regulatory elements that improve adeno-associated virus transgene expression in the brain. Methods 28, 227-236.
Flaherty, K.T., Hodi, F.S., Fisher, D.E., 2012. From genes to drugs: targeted strategies for melanoma. Nat Rev Cancer 12, 349-361.
Folkman, J., 2002. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29, 15-18.
Fortina, A.B., Piaserico, S., Caforio, A.L., Abeni, D., Alaibac, M., Angelini, A., Iliceto, S., Peserico, A., 2004. Immunosuppressive level and other risk factors for basal cell carcinoma and squamous cell carcinoma in heart transplant recipients. Arch Dermatol 140, 1079-1085.
Furuya, M., Yonemitsu, Y., 2008. Cancer neovascularization and proinflammatory microenvironments. Curr Cancer Drug Targets 8, 253-265.
Fuxe, J., Karlsson, M.C., 2012. TGF-beta-induced epithelial-mesenchymal transition: A link between cancer and inflammation. Semin Cancer Biol.
Gantz, I., Fong, T.M., 2003. The melanocortin system. Am J Physiol Endocrinol Metab 284, E468-474.
Gavert, N., Ben-Ze'ev, A., 2008. Epithelial-mesenchymal transition and the invasive potential of tumors. Trends Mol Med 14, 199-209.
Gerstenblith, M.R., Goldstein, A.M., Fargnoli, M.C., Peris, K., Landi, M.T., 2007. Comprehensive evaluation of allele frequency differences of MC1R variants across populations. Hum Mutat 28, 495-505.
Getting, S.J., 2006. Targeting melanocortin receptors as potential novel therapeutics. Pharmacol Ther.
Ghanem, G., Verstegen, J., De Rijcke, S., Hanson, P., Van Onderbergen, A., Libert, A., Del Marmol, V., Arnould, R., Vercammen-Grandjean, A., Lejeune, F., 1989a. Studies on factors influencing human plasma alpha-MSH. Anticancer Res 9, 1691-1696.
Ghanem, G., Verstegen, J., Libert, A., Arnould, R., Lejeune, F., 1989b. Alpha-melanocyte-stimulating hormone immunoreactivity in human melanoma metastases extracts. Pigment Cell Res 2, 519-523.
Grichnik, J.M., 2008. Melanoma, nevogenesis, and stem cell biology. J Invest Dermatol 128, 2365-2380.
Gupta, G.P., Nguyen, D.X., Chiang, A.C., Bos, P.D., Kim, J.Y., Nadal, C., Gomis, R.R., Manova-Todorova, K., Massague, J., 2007. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446, 765-770.
Hadley, M.E., 2005. Discovery that a melanocortin regulates sexual functions in male and female humans. Peptides 26, 1687-1689.
Hadley, M.E., Dorr, R.T., 2006. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides 27, 921-930.
Hatta, N., Dixon, C., Ray, A.J., Phillips, S.R., Cunliffe, W.J., Dale, M., Todd, C., Meggit, S., Birch-MacHin, M.A., Rees, J.L., 2001. Expression, candidate gene, and population studies of the melanocortin 5 receptor. J Invest Dermatol 116, 564-570.
He, T.C., Sparks, A.B., Rago, C., Hermeking, H., Zawel, L., da Costa, L.T., Morin, P.J., Vogelstein, B., Kinzler, K.W., 1998. Identification of c-MYC as a target of the APC pathway. Science 281, 1509-1512.
Heasman, S.J., Ridley, A.J., 2008. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol 9, 690-701.
Hochberg, I., Hochberg, Z., 2010. Hypothalamic obesity. Endocr Dev 17, 185-196.
Hu, T.H., Huang, C.C., Liu, L.F., Lin, P.R., Liu, S.Y., Chang, H.W., Changchien, C.S., Lee, C.M., Chuang, J.H., Tai, M.H., 2003. Expression of hepatoma-derived growth factor in hepatocellular carcinoma. Cancer 98, 1444-1456.
Huang, C.L., Liu, D., Ishikawa, S., Nakashima, T., Nakashima, N., Yokomise, H., Kadota, K., Ueno, M., 2008. Wnt1 overexpression promotes tumour progression in non-small cell lung cancer. Eur J Cancer 44, 2680-2688.
Huszar, D., Lynch, C.A., Fairchild-Huntress, V., Dunmore, J.H., Fang, Q., Berkemeier, L.R., Gu, W., Kesterson, R.A., Boston, B.A., Cone, R.D., Smith, F.J., Campfield, L.A., Burn, P., Lee, F., 1997. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131-141.
Jiang, F., Zhang, G., Hashimoto, I., Kumar, B.S., Bortolotto, S., Morrison, W.A., Dusting, G.J., 2008. Neovascularization in an arterio-venous loop-containing tissue engineering chamber: role of NADPH oxidase. J Cell Mol Med 12, 2062-2072.
Jimenez-Cervantes, C., Germer, S., Gonzalez, P., Sanchez, J., Sanchez, C.O., Garcia-Borron, J.C., 2001. Thr40 and Met122 are new partial loss-of-function natural mutations of the human melanocortin 1 receptor. FEBS Lett 508, 44-48.
Kamai, T., Yamanishi, T., Shirataki, H., Takagi, K., Asami, H., Ito, Y., Yoshida, K., 2004. Overexpression of RhoA, Rac1, and Cdc42 GTPases is associated with progression in testicular cancer. Clin Cancer Res 10, 4799-4805.
Kameyama, K., Vieira, W.D., Tsukamoto, K., Law, L.W., Hearing, V.J., 1990. Differentiation and the tumorigenic and metastatic phenotype of murine melanoma cells. Int J Cancer 45, 1151-1158.
Kerbel, R., Folkman, J., 2002. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2, 727-739.
Klagsbrun, M., Sasse, J., Sullivan, R., Smith, J.A., 1986. Human tumor cells synthesize an endothelial cell growth factor that is structurally related to basic fibroblast growth factor. Proc Natl Acad Sci U S A 83, 2448-2452.
Kleinman, H.K., Jacob, K., 2001. Invasion assays. Curr Protoc Cell Biol Chapter 12, Unit 12 12.
Konda, Y., Gantz, I., DelValle, J., Shimoto, Y., Miwa, H., Yamada, T., 1994. Interaction of dual intracellular signaling pathways activated by the melanocortin-3 receptor. J Biol Chem 269, 13162-13166.
Kronfol, Z., Starkman, M., Schteingart, D.E., Singh, V., Zhang, Q., Hill, E., 1996. Immune regulation in Cushing's syndrome: relationship to hypothalamic-pituitary-adrenal axis hormones. Psychoneuroendocrinology 21, 599-608.
Lam, H.C., Kuo, S.M., Chuang, M.J., Keng, H.M., Lin, P.R., Liu, G.S., Hsu, C.M., Howng, S.L., Tai, M.H., 2006. Blockade of endothelin-1 release contributes to the anti-angiogenic effect by pro-opiomelanocortin overexpression in endothelial cells. Exp Biol Med (Maywood) 231, 782-788.
Langan, E.A., Nie, Z., Rhodes, L.E., 2010. Melanotropic peptides: more than just 'Barbie drugs' and 'sun-tan jabs'? Br J Dermatol 163, 451-455.
Lee, K.H., Choi, E.Y., Kim, M.K., Lee, S.H., Jang, B.I., Kim, T.N., Kim, S.W., Song, S.K., Kim, J.R., Jung, B.C., 2011. Hepatoma-derived growth factor regulates the bad-mediated apoptotic pathway and induction of vascular endothelial growth factor in stomach cancer cells. Oncol Res 19, 67-76.
Levayer, R., Lecuit, T., 2008. Breaking down EMT. Nat Cell Biol 10, 757-759.
Libert, A., Ghanem, G., Arnould, R., Lejeune, F.J., 1989. Use of an alpha-melanocyte-stimulating hormone analogue to improve alpha-melanocyte-stimulating hormone receptor binding assay in human melanoma. Pigment Cell Res 2, 510-518.
Lin, C.R., Yang, L.C., Lee, T.H., Lee, C.T., Huang, H.T., Sun, W.Z., Cheng, J.T., 2002. Electroporation-mediated pain-killer gene therapy for mononeuropathic rats. Gene Ther 9, 1247-1253.
Lindelof, B., Sigurgeirsson, B., Gabel, H., Stern, R.S., 2000. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol 143, 513-519.
Liu, G.S., Huang, H.T., Lin, C.J., Shi, J.Y., Liu, L.F., Tseng, R.T., Weng, W.T., Lam, H.C., Wen, Z.H., Cheng, T.L., Hsu, K.S., Tai, M.H., 2009. Prophylactic proopiomelanocortin expression alleviates capsaicin-induced neurogenic inflammation in rat trachea. Shock 32, 645-650.
Liu, G.S., Liu, L.F., Lin, C.J., Tseng, J.C., Chuang, M.J., Lam, H.C., Lee, J.K., Yang, L.C., Chan, J.H., Howng, S.L., Tai, M.H., 2006. Gene transfer of pro-opiomelanocortin prohormone suppressed the growth and metastasis of melanoma: involvement of alpha-melanocyte-stimulating hormone-mediated inhibition of the nuclear factor kappaB/cyclooxygenase-2 pathway. Mol Pharmacol 69, 440-451.
Liu, G.S., Tsai, H.E., Weng, W.T., Liu, L.F., Weng, C.H., Chuang, M.R., Lam, H.C., Wu, C.S., Tee, R., Wen, Z.H., Howng, S.L., Tai, M.H., 2011. Systemic Pro-opiomelanocortin Expression Induces Melanogenic Differentiation and Inhibits Tumor Angiogenesis in Established Mouse Melanoma. Hum Gene Ther 22, 325-335.
Luger, T.A., Bhardwaj, R.S., Grabbe, S., Schwarz, T., 1996. Regulation of the immune response by epidermal cytokines and neurohormones. J Dermatol Sci 13, 5-10.
Luger, T.A., Kalden, D., Scholzen, T.E., Brzoska, T., 1999. alpha-melanocyte-stimulating hormone as a mediator of tolerance induction. Pathobiology 67, 318-321.
Luger, T.A., Scholzen, T., Brzoska, T., Becher, E., Slominski, A., Paus, R., 1998. Cutaneous immunomodulation and coordination of skin stress responses by alpha-melanocyte-stimulating hormone. Ann N Y Acad Sci 840, 381-394.
Luger, T.A., Scholzen, T.E., Brzoska, T., Bohm, M., 2003. New insights into the functions of alpha-MSH and related peptides in the immune system. Ann N Y Acad Sci 994, 133-140.
Maaser, C., Kannengiesser, K., Specht, C., Luegering, A., Brzoska, T., Luger, T.A., Domschke, W., Kucharzik, T., 2006. Crucial role of the melanocortin receptor MC1R in experimental colitis. Gut.
Machiels, J.P., van Baren, N., Marchand, M., 2002. Peptide-based cancer vaccines. Semin Oncol 29, 494-502.
Mahabeleshwar, G.H., Byzova, T.V., 2007. Angiogenesis in melanoma. Semin Oncol 34, 555-565.
Malagoli, D., Accorsi, A., Ottaviani, E., 2011. The evolution of pro-opiomelanocortin: looking for the invertebrate fingerprints. Peptides 32, 2137-2140.
Mantovani, A., Sozzani, S., Locati, M., Allavena, P., Sica, A., 2002. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23, 549-555.
Matichard, E., Verpillat, P., Meziani, R., Gerard, B., Descamps, V., Legroux, E., Burnouf, M., Bertrand, G., Bouscarat, F., Archimbaud, A., Picard, C., Ollivaud, L., Basset-Seguin, N., Kerob, D., Lanternier, G., Lebbe, C., Crickx, B., Grandchamp, B., Soufir, N., 2004. Melanocortin 1 receptor (MC1R) gene variants may increase the risk of melanoma in France independently of clinical risk factors and UV exposure. J Med Genet 41, e13.
Miller, A.J., Mihm, M.C., Jr., 2006. Melanoma. N Engl J Med 355, 51-65.
Miller, W.L., 2007. Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter. Biochim Biophys Acta 1771, 663-676.
Minn, A.J., Gupta, G.P., Siegel, P.M., Bos, P.D., Shu, W., Giri, D.D., Viale, A., Olshen, A.B., Gerald, W.L., Massague, J., 2005. Genes that mediate breast cancer metastasis to lung. Nature 436, 518-524.
Mornet, E., Dupont, J., Vitek, A., White, P.C., 1989. Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta). J Biol Chem 264, 20961-20967.
Mountjoy, K.G., Robbins, L.S., Mortrud, M.T., Cone, R.D., 1992. The cloning of a family of genes that encode the melanocortin receptors. Science 257, 1248-1251.
Murata, J., Ayukawa, K., Ogasawara, M., Fujii, H., Saiki, I., 1997. Alpha-melanocyte-stimulating hormone blocks invasion of reconstituted basement membrane (Matrigel) by murine B16 melanoma cells. Invasion Metastasis 17, 82-93.
Nakamura, H., Izumoto, Y., Kambe, H., Kuroda, T., Mori, T., Kawamura, K., Yamamoto, H., Kishimoto, T., 1994. Molecular cloning of complementary DNA for a novel human hepatoma-derived growth factor. Its homology with high mobility group-1 protein. J Biol Chem 269, 25143-25149.
Nakamura, H., Kambe, H., Egawa, T., Kimura, Y., Ito, H., Hayashi, E., Yamamoto, H., Sato, J., Kishimoto, S., 1989. Partial purification and characterization of human hepatoma-derived growth factor. Clin Chim Acta 183, 273-284.
Nakamura, M., Tokura, Y., 2010. Epithelial-mesenchymal transition in the skin. J Dermatol Sci 61, 7-13.
Nakanishi, S., Inoue, A., Kita, T., Nakamura, M., Chang, A.C., Cohen, S.N., Numa, S., 1979. Nucleotide sequence of cloned cDNA for bovine corticotropin-beta-lipotropin precursor. Nature 278, 423-427.
Newton, R., 2000. Molecular mechanisms of glucocorticoid action: what is important? Thorax 55, 603-613.
Nimkarn, S., New, M.I., 2008. Steroid 11beta- hydroxylase deficiency congenital adrenal hyperplasia. Trends Endocrinol Metab 19, 96-99.
Otley, C.C., Coldiron, B.M., Stasko, T., Goldman, G.D., 2001. Decreased skin cancer after cessation of therapy with transplant-associated immunosuppressants. Arch Dermatol 137, 459-463.
Pantel, K., Brakenhoff, R.H., 2004. Dissecting the metastatic cascade. Nat Rev Cancer 4, 448-456.
Paul, S., Dey, A., 2008. Wnt signaling and cancer development: therapeutic implication. Neoplasma 55, 165-176.
Peris, K., Fargnoli, M.C., Pacifico, A., Surrenti, T., Stolz, W., Wolf, P., Soyer, H.P., Chimenti, S., 2004. CDKN2A and MC1R mutations in patients with sporadic multiple primary melanoma. J Invest Dermatol 122, 1327-1330.
Pure, E., Allison, J.P., Schreiber, R.D., 2005. Breaking down the barriers to cancer immunotherapy. Nat Immunol 6, 1207-1210.
Raffin-Sanson, M.L., de Keyzer, Y., Bertagna, X., 2003. Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions. Eur J Endocrinol 149, 79-90.
Rainey, W.E., Saner, K., Schimmer, B.P., 2004. Adrenocortical cell lines. Mol Cell Endocrinol 228, 23-38.
Rana, B.K., 2003. New insights into G-protein-coupled receptor signaling from the melanocortin receptor system. Mol Pharmacol 64, 1-4.
Refojo, D., Kovalovsky, D., Young, J.I., Rubinstein, M., Holsboer, F., Reul, J.M., Low, M.J., Arzt, E., 2002. Increased splenocyte proliferative response and cytokine production in beta-endorphin-deficient mice. J Neuroimmunol 131, 126-134.
Riker, A.I., Radfar, S., Liu, S., Wang, Y., Khong, H.T., 2007. Immunotherapy of melanoma: a critical review of current concepts and future strategies. Expert Opin Biol Ther 7, 345-358.
Robbins, L.S., Nadeau, J.H., Johnson, K.R., Kelly, M.A., Roselli-Rehfuss, L., Baack, E., Mountjoy, K.G., Cone, R.D., 1993. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 72, 827-834.
Robinson, S.J., Healy, E., 2002. Human melanocortin 1 receptor (MC1R) gene variants alter melanoma cell growth and adhesion to extracellular matrix. Oncogene 21, 8037-8046.
Rouzaud, F., Kadekaro, A.L., Abdel-Malek, Z.A., Hearing, V.J., 2005. MC1R and the response of melanocytes to ultraviolet radiation. Mutat Res 571, 133-152.
Sahai, E., 2007. Illuminating the metastatic process. Nat Rev Cancer 7, 737-749.
Schioth, H.B., Chhajlani, V., Muceniece, R., Klusa, V., Wikberg, J.E., 1996. Major pharmacological distinction of the ACTH receptor from other melanocortin receptors. Life Sci 59, 797-801.
Scott, G., 2002. Rac and rho: the story behind melanocyte dendrite formation. Pigment Cell Res 15, 322-330.
Sedlmaier, A., Wernert, N., Gallitzendorfer, R., Abouzied, M.M., Gieselmann, V., Franken, S., Overexpression of hepatoma-derived growth factor in melanocytes does not lead to oncogenic transformation. BMC Cancer 11, 457.
Shackleton, C.H., Hughes, B.A., Lavery, G.G., Walker, E.A., Stewart, P.M., 2008. The corticosteroid metabolic profile of the mouse. Steroids 73, 1066-1076.
Slominski, A., Tobin, D.J., Shibahara, S., Wortsman, J., 2004. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 84, 1155-1228.
Smalley, K., Eisen, T., 2000. The involvement of p38 mitogen-activated protein kinase in the alpha-melanocyte stimulating hormone (alpha-MSH)-induced melanogenic and anti-proliferative effects in B16 murine melanoma cells. FEBS Lett 476, 198-202.
Smalley, K.S., Eisen, T.G., 2002. Differentiation of human melanoma cells through p38 MAP kinase is associated with decreased retinoblastoma protein phosphorylation and cell cycle arrest. Melanoma Res 12, 187-192.
Soderholm, J., Heald, R., 2005. Scratch n' screen for inhibitors of cell migration. Chem Biol 12, 263-265.
Soengas, M.S., Lowe, S.W., 2003. Apoptosis and melanoma chemoresistance. Oncogene 22, 3138-3151.
Solomon, S., 1999. POMC-derived peptides and their biological action. Ann N Y Acad Sci 885, 22-40.
Steeg, P.S., 2006. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12, 895-904.
Stratigos, A.J., Dimisianos, G., Nikolaou, V., Poulou, M., Sypsa, V., Stefanaki, I., Papadopoulos, O., Polydorou, D., Plaka, M., Christofidou, E., Gogas, H., Tsoutsos, D., Kastana, O., Antoniou, C., Hatzakis, A., Kanavakis, E., Katsambas, A.D., 2006. Melanocortin receptor-1 gene polymorphisms and the risk of cutaneous melanoma in a low-risk southern European population. J Invest Dermatol 126, 1842-1849.
Taherzadeh, S., Sharma, S., Chhajlani, V., Gantz, I., Rajora, N., Demitri, M.T., Kelly, L., Zhao, H., Ichiyama, T., Catania, A., Lipton, J.M., 1999. alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte/macrophages. Am J Physiol 276, R1289-1294.
Tai, M.H., Cheng, H., Wu, J.P., Liu, Y.L., Lin, P.R., Kuo, J.S., Tseng, C.J., Tzeng, S.F., 2003. Gene transfer of glial cell line-derived neurotrophic factor promotes functional recovery following spinal cord contusion. Exp Neurol 183, 508-515.
Tai, M.H., Wang, L.L., Wu, K.L., Chan, J.Y., 2005. Increased superoxide anion in rostral ventrolateral medulla contributes to hypertension in spontaneously hypertensive rats via interactions with nitric oxide. Free Radic Biol Med 38, 450-462.
Tatro, J.B., 1996. Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides. Neuroimmunomodulation 3, 259-284.
Tetsu, O., McCormick, F., 1999. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422-426.
Thiery, J.P., 2002. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2, 442-454.
Todorovic, A., Haskell-Luevano, C., 2005. A review of melanocortin receptor small molecule ligands. Peptides 26, 2026-2036.
Tsai, C.N., Tsai, C.L., Tse, K.P., Chang, H.Y., Chang, Y.S., 2002. The Epstein-Barr virus oncogene product, latent membrane protein 1, induces the downregulation of E-cadherin gene expression via activation of DNA methyltransferases. Proc Natl Acad Sci U S A 99, 10084-10089.
Tsai, H.E., Liu, L.F., Dusting, G.J., Weng, W.T., Chen, S.C., Kung, M.L., Tee, R., Liu, G.S., Tai, M.H., 2012. Pro-opiomelanocortin gene delivery suppresses the growth of established Lewis lung carcinoma through a melanocortin-1 receptor-independent pathway. J Gene Med 14, 44-53.
Uematsu, K., He, B., You, L., Xu, Z., McCormick, F., Jablons, D.M., 2003. Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression. Oncogene 22, 7218-7221.
Vakkila, J., Lotze, M.T., 2004. Inflammation and necrosis promote tumour growth. Nat Rev Immunol 4, 641-648.
Vallacchi, V., Daniotti, M., Ratti, F., Di Stasi, D., Deho, P., De Filippo, A., Tragni, G., Balsari, A., Carbone, A., Rivoltini, L., Parmiani, G., Lazar, N., Perbal, B., Rodolfo, M., 2008. CCN3/nephroblastoma overexpressed matricellular protein regulates integrin expression, adhesion, and dissemination in melanoma. Cancer Res 68, 715-723.
Van Aelst, L., Symons, M., 2002. Role of Rho family GTPases in epithelial morphogenesis. Genes Dev 16, 1032-1054.
Vega, F.M., Ridley, A.J., 2008. Rho GTPases in cancer cell biology. FEBS Lett 582, 2093-2101.
Vinson, G.P., 2009. The adrenal cortex and life. Mol Cell Endocrinol 300, 2-6.
Wachira, S.J., Hughes-Darden, C.A., Taylor, C.V., Ochillo, R., Robinson, T.J., 2003. Evidence for the interaction of protein kinase C and melanocortin 3-receptor signaling pathways. Neuropeptides 37, 201-210.
Wang, H., Fu, W., Im, J.H., Zhou, Z., Santoro, S.A., Iyer, V., DiPersio, C.M., Yu, Q.C., Quaranta, V., Al-Mehdi, A., Muschel, R.J., 2004. Tumor cell alpha3beta1 integrin and vascular laminin-5 mediate pulmonary arrest and metastasis. J Cell Biol 164, 935-941.
Wikberg, J.E., Muceniece, R., Mandrika, I., Prusis, P., Lindblom, J., Post, C., Skottner, A., 2000. New aspects on the melanocortins and their receptors. Pharmacol Res 42, 393-420.
Wu, Y., Zhou, B.P., 2008. New insights of epithelial-mesenchymal transition in cancer metastasis. Acta Biochim Biophys Sin (Shanghai) 40, 643-650.
Xiao, D., He, J., 2010. Epithelial mesenchymal transition and lung cancer. J Thorac Dis 2, 154-159.
Xu, J., Lamouille, S., Derynck, R., 2009. TGF-beta-induced epithelial to mesenchymal transition. Cell Res 19, 156-172.
Yamamoto, S., Tomita, Y., Hoshida, Y., Morii, E., Yasuda, T., Doki, Y., Aozasa, K., Uyama, H., Nakamura, H., Monden, M., 2007. Expression level of hepatoma-derived growth factor correlates with tumor recurrence of esophageal carcinoma. Ann Surg Oncol 14, 2141-2149.
Yamamoto, T., Nakamura, H., Liu, W., Cao, K., Yoshikawa, S., Enomoto, H., Iwata, Y., Koh, N., Saito, M., Imanishi, H., Shimomura, S., Iijima, H., Hada, T., Nishiguchi, S., 2009. Involvement of hepatoma-derived growth factor in the growth inhibition of hepatocellular carcinoma cells by vitamin K(2). J Gastroenterol 44, 228-235.
Ye, P., Kenyon, C.J., Mackenzie, S.M., Nichol, K., Seckl, J.R., Fraser, R., Connell, J.M., Davies, E., 2008. Effects of ACTH, dexamethasone, and adrenalectomy on 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) gene expression in the rat central nervous system. J Endocrinol 196, 305-311.
Young, J.W., Inaba, K., 1996. Dendritic cells as adjuvants for class I major histocompatibility complex-restricted antitumor immunity. J Exp Med 183, 7-11.
Zattra, E., Fortina, A.B., Bordignon, M., Piaserico, S., Alaibac, M., 2009. Immunosuppression and melanocyte proliferation. Melanoma Res 19, 63-68.
Zhao, H., Hastie, T., Whitfield, M.L., Borresen-Dale, A.L., Jeffrey, S.S., 2002. Optimization and evaluation of T7 based RNA linear amplification protocols for cDNA microarray analysis. BMC Genomics 3, 31.
Zhu, N., Lalla, R., Eves, P., Brown, T.L., King, A., Kemp, E.H., Haycock, J.W., MacNeil, S., 2004. Melanoma cell migration is upregulated by tumour necrosis factor-alpha and suppressed by alpha-melanocyte-stimulating hormone. Br J Cancer 90, 1457-1463.
Ziegler, A., Jonason, A.S., Leffell, D.J., Simon, J.A., Sharma, H.W., Kimmelman, J., Remington, L., Jacks, T., Brash, D.E., 1994. Sunburn and p53 in the onset of skin cancer. Nature 372, 773-776.