Prevention of Melanoma Extravasation as a New Treatment Option Exemplified by p38/MK2 Inhibition
Abstract
:1. Melanoma Dissemination
2. Melanoma Extravasation
2.1. The Rolling and Adhesion Step
2.2. The Extravasation Step
3. Phenotypic Plasticity of Melanoma
The MAP Kinase Pathways
4. Melanoma/Endothelial Interaction
5. Therapeutic Outlook
6. Conclusions
Funding
Conflicts of Interest
Abbreviations
AKT | protein kinase B |
AXL | receptor protein-tyrosine kinase |
BRAF | serine/threonine-protein kinase B-Raf |
DEL-1 | developmental endothelial locus-1 |
ESAM | endothelial cell-selective adhesion molecule |
FAK | fokal adhesion kinase |
GLI2 | GLI family zinc finger 2 |
JAK | Janus kinase |
JAM | junctional adhesion molecule |
JARID1B | histone demethylase, also known as lysine-specific demethylase 5B |
MAP | microtubule-associated proteins |
MITF | microphthalmia-associated transcription factor |
MK2 | mitogen-activated protein kinase-activated protein kinase 2 |
mTOR | mechanistic target of Rapamycin |
p38 | p38-mitogenactivated protein kinases |
PI3K | Phosphoinositide 3-kinases |
PODXL | podocalyxin-like protein 1 |
SMO | Smoothened |
SNAI1 | Zinc finger protein SNAI1 |
SPARC | secreted protein acidic and rich in cysteine also known as Osteonectin |
STAT3 | signal transducer and activator of transcription3 |
THBS1 | thrombospondin 1 |
TWIST1 | Twist-related protein 1 |
VCAM-1 | vascular cell adhesion molecule 1 |
VEGF-C | vascular endothelial growth factor C |
References
- Rinderknecht, M.; Detmar, M. Tumor lymphangiogenesis and melanoma metastasis. J. Cell Physiol. 2008, 216, 347–354. [Google Scholar] [CrossRef] [PubMed]
- Carmeliet, P.; Jain, R.K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug Discov. 2011, 10, 417–427. [Google Scholar] [CrossRef] [PubMed]
- Pastushenko, I.; Vermeulen, P.B.; Carapeto, F.J.; Van den Eynden, G.; Rutten, A.; Ara, M.; Dirix, L.Y.; Van Laere, S. Blood microvessel density, lymphatic microvessel density and lymphatic invasion in predicting melanoma metastases: Systematic review and meta-analysis. Br. J. Dermatol. 2014, 170, 66–77. [Google Scholar] [CrossRef] [PubMed]
- Kerjaschki, D.; Bago-Horvath, Z.; Rudas, M.; Sexl, V.; Schneckenleithner, C.; Wolbank, S.; Bartel, G.; Krieger, S.; Kalt, R.; Hantusch, B.; et al. Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse. J. Clin. Investig. 2011, 121, 2000–2012. [Google Scholar] [CrossRef]
- Pflicke, H.; Sixt, M. Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. J. Exp. Med. 2009, 206, 2925–2935. [Google Scholar] [CrossRef] [Green Version]
- Alitalo, A.; Detmar, M. Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene 2012, 31, 4499–4508. [Google Scholar] [CrossRef] [Green Version]
- Fidler, I.J. Metastasis: Quantitative analysis of distribution and fate of tumor emboli labeled with 125 I-5-iodo-2’-deoxyuridine. J. Natl. Cancer Inst. 1970, 45, 773–782. [Google Scholar] [PubMed]
- Moose, D.L.; Krog, B.L.; Kim, T.H.; Zhao, L.; Williams-Perez, S.; Burke, G.; Rhodes, L.; Vanneste, M.; Breheny, P.; Milhem, M.; et al. Cancer Cells Resist Mechanical Destruction in Circulation via RhoA/Actomyosin-Dependent Mechano-Adaptation. Cell Rep. 2020, 30, 3864–3874 e3866. [Google Scholar] [CrossRef]
- Foss, A.; Munoz-Sagredo, L.; Sleeman, J.; Thiele, W. The contribution of platelets to intravascular arrest, extravasation, and outgrowth of disseminated tumor cells. Clin. Exp. Metastasis 2020, 37, 47–67. [Google Scholar] [CrossRef]
- Fofaria, N.M.; Srivastava, S.K. Critical role of STAT3 in melanoma metastasis through anoikis resistance. Oncotarget 2014, 5, 7051–7064. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Strilic, B.; Offermanns, S. Intravascular Survival and Extravasation of Tumor Cells. Cancer Cell 2017, 32, 282–293. [Google Scholar] [CrossRef]
- Jahanban-Esfahlan, R.; Seidi, K.; Manjili, M.H.; Jahanban-Esfahlan, A.; Javaheri, T.; Zare, P. Tumor Cell Dormancy: Threat or Opportunity in the Fight against Cancer. Cancers 2019, 11, 1207. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wood, S., Jr. Pathogenesis of metastasis formation observed in vivo in the rabbit ear chamber. AMA Arch. Pathol. 1958, 66, 550–568. [Google Scholar] [PubMed]
- Zeidman, I. The fate of circulating tumors cells. I. Passage of cells through capillaries. Cancer Res. 1961, 21, 38–39. [Google Scholar] [PubMed]
- Lawrence, M.B.; Bainton, D.F.; Springer, T.A. Neutrophil tethering to and rolling on E-selectin are separable by requirement for L-selectin. Immunity 1994, 1, 137–145. [Google Scholar] [CrossRef]
- Umemoto, E.; Hayasaka, H.; Bai, Z.; Cai, L.; Yonekura, S.; Peng, X.; Takeda, A.; Tohya, K.; Miyasaka, M. Novel regulators of lymphocyte trafficking across high endothelial venules. Crit. Rev. Immunol. 2011, 31, 147–169. [Google Scholar] [CrossRef]
- Fitzgerald, J.F.; Byrd, B.K.; Patil, R.A.; Strawbridge, R.R.; Davis, S.C.; Bellini, C.; Niedre, M. Heterogeneity of circulating tumor cell dissemination and lung metastases in a subcutaneous Lewis lung carcinoma model. Biomed. Opt. Express 2020, 11, 3633–3647. [Google Scholar] [CrossRef] [PubMed]
- Jin, F.; Wang, F. The physiological and pathological roles and applications of sialyl Lewis x, a common carbohydrate ligand of the three selectins. Glycoconj. J. 2020, 37, 277–291. [Google Scholar] [CrossRef]
- Liang, S.; Dong, C. Integrin VLA-4 enhances sialyl-Lewisx/a-negative melanoma adhesion to and extravasation through the endothelium under low flow conditions. Am. J. Physiol. Cell Physiol. 2008, 295, C701–C707. [Google Scholar] [CrossRef] [Green Version]
- Okahara, H.; Yagita, H.; Miyake, K.; Okumura, K. Involvement of very late activation antigen 4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) in tumor necrosis factor alpha enhancement of experimental metastasis. Cancer Res. 1994, 54, 3233–3236. [Google Scholar] [PubMed]
- Rice, G.E.; Bevilacqua, M.P. An inducible endothelial cell surface glycoprotein mediates melanoma adhesion. Science 1989, 246, 1303–1306. [Google Scholar] [CrossRef]
- Tichet, M.; Prod’Homme, V.; Fenouille, N.; Ambrosetti, D.; Mallavialle, A.; Cerezo, M.; Ohanna, M.; Audebert, S.; Rocchi, S.; Giacchero, D.; et al. Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis. Nat. Commun. 2015, 6, 6993. [Google Scholar] [CrossRef] [Green Version]
- Vestweber, D. How leukocytes cross the vascular endothelium. Nat. Rev. Immunol. 2015, 15, 692–704. [Google Scholar] [CrossRef]
- Langer, H.F.; Orlova, V.V.; Xie, C.; Kaul, S.; Schneider, D.; Lonsdorf, A.S.; Fahrleitner, M.; Choi, E.Y.; Dutoit, V.; Pellegrini, M.; et al. A novel function of junctional adhesion molecule-C in mediating melanoma cell metastasis. Cancer Res. 2011, 71, 4096–4105. [Google Scholar] [CrossRef] [Green Version]
- Jouve, N.; Bachelier, R.; Despoix, N.; Blin, M.G.; Matinzadeh, M.K.; Poitevin, S.; Aurrand-Lions, M.; Fallague, K.; Bardin, N.; Blot-Chabaud, M.; et al. CD146 mediates VEGF-induced melanoma cell extravasation through FAK activation. Int. J. Cancer 2015, 137, 50–60. [Google Scholar] [CrossRef]
- Melnikova, V.O.; Balasubramanian, K.; Villares, G.J.; Dobroff, A.S.; Zigler, M.; Wang, H.; Petersson, F.; Price, J.E.; Schroit, A.; Prieto, V.G.; et al. Crosstalk between protease-activated receptor 1 and platelet-activating factor receptor regulates melanoma cell adhesion molecule (MCAM/MUC18) expression and melanoma metastasis. J. Biol. Chem. 2009, 284, 28845–28855. [Google Scholar] [CrossRef] [Green Version]
- Rambow, F.; Marine, J.C.; Goding, C.R. Melanoma plasticity and phenotypic diversity: Therapeutic barriers and opportunities. Genes Dev. 2019, 33, 1295–1318. [Google Scholar] [CrossRef] [Green Version]
- Roesch, A.; Fukunaga-Kalabis, M.; Schmidt, E.C.; Zabierowski, S.E.; Brafford, P.A.; Vultur, A.; Basu, D.; Gimotty, P.; Vogt, T.; Herlyn, M. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 2010, 141, 583–594. [Google Scholar] [CrossRef] [Green Version]
- Tirosh, I.; Izar, B.; Prakadan, S.M.; Wadsworth, M.H., 2nd; Treacy, D.; Trombetta, J.J.; Rotem, A.; Rodman, C.; Lian, C.; Murphy, G.; et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 2016, 352, 189–196. [Google Scholar] [CrossRef] [Green Version]
- Gay, C.M.; Balaji, K.; Byers, L.A. Giving AXL the axe: Targeting AXL in human malignancy. Br. J. Cancer 2017, 116, 415–423. [Google Scholar] [CrossRef]
- Widmer, D.S.; Cheng, P.F.; Eichhoff, O.M.; Belloni, B.C.; Zipser, M.C.; Schlegel, N.C.; Javelaud, D.; Mauviel, A.; Dummer, R.; Hoek, K.S. Systematic classification of melanoma cells by phenotype-specific gene expression mapping. Pigment Cell Melanoma Res. 2012, 25, 343–353. [Google Scholar] [CrossRef]
- Hoek, K.S.; Eichhoff, O.M.; Schlegel, N.C.; Dobbeling, U.; Kobert, N.; Schaerer, L.; Hemmi, S.; Dummer, R. In vivo switching of human melanoma cells between proliferative and invasive states. Cancer Res. 2008, 68, 650–656. [Google Scholar] [CrossRef] [Green Version]
- Davies, H.; Bignell, G.R.; Cox, C.; Stephens, P.; Edkins, S.; Clegg, S.; Teague, J.; Woffendin, H.; Garnett, M.J.; Bottomley, W.; et al. Mutations of the BRAF gene in human cancer. Nature 2002, 417, 949–954. [Google Scholar] [CrossRef]
- Sensi, M.; Catani, M.; Castellano, G.; Nicolini, G.; Alciato, F.; Tragni, G.; De Santis, G.; Bersani, I.; Avanzi, G.; Tomassetti, A.; et al. Human cutaneous melanomas lacking MITF and melanocyte differentiation antigens express a functional Axl receptor kinase. J. Investig. Dermatol. 2011, 131, 2448–2457. [Google Scholar] [CrossRef] [Green Version]
- Wagner, E.F.; Nebreda, A.R. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat. Rev. Cancer 2009, 9, 537–549. [Google Scholar] [CrossRef]
- Hammouda, M.B.; Ford, A.E.; Liu, Y.; Zhang, J.Y. The JNK Signaling Pathway in Inflammatory Skin Disorders and Cancer. Cells 2020, 9, 857. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Puujalka, E.; Heinz, M.; Hoesel, B.; Friedl, P.; Schweighofer, B.; Wenzina, J.; Pirker, C.; Schmid, J.A.; Loewe, R.; Wagner, E.F.; et al. Opposing Roles of JNK and p38 in Lymphangiogenesis in Melanoma. J. Investig. Dermatol. 2016, 136, 967–977. [Google Scholar] [CrossRef] [Green Version]
- Lopez-Bergami, P. The role of mitogen- and stress-activated protein kinase pathways in melanoma. Pigment Cell Melanoma Res. 2011, 24, 902–921. [Google Scholar] [CrossRef]
- DeNicola, G.F.; Martin, E.D.; Chaikuad, A.; Bassi, R.; Clark, J.; Martino, L.; Verma, S.; Sicard, P.; Tata, R.; Atkinson, R.A.; et al. Mechanism and consequence of the autoactivation of p38alpha mitogen-activated protein kinase promoted by TAB1. Nat. Struct. Mol. Biol. 2013, 20, 1182–1190. [Google Scholar] [CrossRef] [Green Version]
- Salvador, J.M.; Mittelstadt, P.R.; Guszczynski, T.; Copeland, T.D.; Yamaguchi, H.; Appella, E.; Fornace, A.J.; Ashwell, J.D., Jr. Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Nat. Immunol. 2005, 6, 390–395. [Google Scholar] [CrossRef]
- Zarubin, T.; Han, J. Activation and signaling of the p38 MAP kinase pathway. Cell Res. 2005, 15, 11–18. [Google Scholar] [CrossRef] [Green Version]
- Afasizheva, A.; Devine, A.; Tillman, H.; Fung, K.L.; Vieira, W.D.; Blehm, B.H.; Kotobuki, Y.; Busby, B.; Chen, E.I.; Tanner, K. Mitogen-activated protein kinase signaling causes malignant melanoma cells to differentially alter extracellular matrix biosynthesis to promote cell survival. BMC Cancer 2016, 16, 186. [Google Scholar] [CrossRef] [Green Version]
- Linnskog, R.; Jonsson, G.; Axelsson, L.; Prasad, C.P.; Andersson, T. Interleukin-6 drives melanoma cell motility through p38alpha-MAPK-dependent up-regulation of WNT5A expression. Mol. Oncol. 2014, 8, 1365–1378. [Google Scholar] [CrossRef]
- Wen, S.Y.; Cheng, S.Y.; Ng, S.C.; Aneja, R.; Chen, C.J.; Huang, C.Y.; Kuo, W.W. Roles of p38alpha and p38beta mitogenactivated protein kinase isoforms in human malignant melanoma A375 cells. Int. J. Mol. Med. 2019, 44, 2123–2132. [Google Scholar]
- Kuphal, S.; Poser, I.; Jobin, C.; Hellerbrand, C.; Bosserhoff, A.K. Loss of E-cadherin leads to upregulation of NFkappaB activity in malignant melanoma. Oncogene 2004, 23, 8509–8519. [Google Scholar] [CrossRef] [Green Version]
- Wenzina, J.; Holzner, S.; Puujalka, E.; Cheng, P.F.; Forsthuber, A.; Neumuller, K.; Schossleitner, K.; Lichtenberger, B.M.; Levesque, M.P.; Petzelbauer, P. Inhibition of p38/MK2 Signaling Prevents Vascular Invasion of Melanoma. J. Investig. Dermatol. 2020, 140, 878–890 e875. [Google Scholar] [CrossRef]
- Avtanski, D.B.; Nagalingam, A.; Bonner, M.Y.; Arbiser, J.L.; Saxena, N.K.; Sharma, D. Honokiol inhibits epithelial-mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3/Zeb1/E-cadherin axis. Mol. Oncol. 2014, 8, 565–580. [Google Scholar] [CrossRef]
- Llorens, M.C.; Lorenzatti, G.; Cavallo, N.L.; Vaglienti, M.V.; Perrone, A.P.; Carenbauer, A.L.; Darling, D.S.; Cabanillas, A.M. Phosphorylation Regulates Functions of ZEB1 Transcription Factor. J. Cell Physiol. 2016, 231, 2205–2217. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Atkinson, P.J.; Dellovade, T.; Albers, D.; Von Schack, D.; Saraf, K.; Needle, E.; Reinhart, P.H.; Hirst, W.D. Sonic Hedgehog signaling in astrocytes is dependent on p38 mitogen-activated protein kinase and G-protein receptor kinase 2. J. Neurochem. 2009, 108, 1539–1549. [Google Scholar] [CrossRef]
- Javelaud, D.; Alexaki, V.I.; Dennler, S.; Mohammad, K.S.; Guise, T.A.; Mauviel, A. TGF-beta/SMAD/GLI2 signaling axis in cancer progression and metastasis. Cancer Res. 2011, 71, 5606–5610. [Google Scholar] [CrossRef] [Green Version]
- Katoh, Y.; Katoh, M. Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). Int. J. Mol. Med. 2008, 22, 271–275. [Google Scholar] [CrossRef] [Green Version]
- Cannonier, S.A.; Gonzales, C.B.; Ely, K.; Guelcher, S.A.; Sterling, J.A. Hedgehog and TGFbeta signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma. Oncotarget 2016, 7, 76062–76075. [Google Scholar] [CrossRef] [Green Version]
- Perrot, C.Y.; Gilbert, C.; Marsaud, V.; Postigo, A.; Javelaud, D.; Mauviel, A. GLI2 cooperates with ZEB1 for transcriptional repression of CDH1 expression in human melanoma cells. Pigment Cell Melanoma Res. 2013, 26, 861–873. [Google Scholar] [CrossRef] [PubMed]
- Du, W.; Liu, X.; Fan, G.; Zhao, X.; Sun, Y.; Wang, T.; Zhao, R.; Wang, G.; Zhao, C.; Zhu, Y.; et al. From cell membrane to the nucleus: An emerging role of E-cadherin in gene transcriptional regulation. J. Cell Mol. Med. 2014, 18, 1712–1719. [Google Scholar] [CrossRef]
- Joshi, S.S.; Hornyak, T.J. Cellular Phenotypic Plasticity of Cutaneous Melanoma: A Complex Puzzle. J. Investig. Dermatol. 2020, 140, 743–745. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jeong, D.; Ban, S.; Oh, S.; Lee, S.J.; Park, S.Y.; Koh, Y.W. Prognostic Significance of EDIL3 Expression and Correlation with Mesenchymal Phenotype and Microvessel Density in Lung Adenocarcinoma. Sci. Rep. 2017, 7, 8649. [Google Scholar] [CrossRef]
- Boman, K.; Andersson, G.; Wennersten, C.; Nodin, B.; Ahlgren, G.; Jirstrom, K. Podocalyxin-like and RNA-binding motif protein 3 are prognostic biomarkers in urothelial bladder cancer: A validatory study. Biomark Res. 2017, 5, 10. [Google Scholar] [CrossRef] [Green Version]
- Kaprio, T.; Fermer, C.; Hagstrom, J.; Mustonen, H.; Bockelman, C.; Nilsson, O.; Haglund, C. Podocalyxin is a marker of poor prognosis in colorectal cancer. BMC Cancer 2014, 14, 493. [Google Scholar] [CrossRef] [Green Version]
- Taniuchi, K.; Furihata, M.; Naganuma, S.; Dabanaka, K.; Hanazaki, K.; Saibara, T. Podocalyxin-like protein, linked to poor prognosis of pancreatic cancers, promotes cell invasion by binding to gelsolin. Cancer Sci. 2016, 107, 1430–1442. [Google Scholar] [CrossRef]
- Larrucea, S.; Butta, N.; Arias-Salgado, E.G.; Alonso-Martin, S.; Ayuso, M.S.; Parrilla, R. Expression of podocalyxin enhances the adherence, migration, and intercellular communication of cells. Exp. Cell Res. 2008, 314, 2004–2015. [Google Scholar] [CrossRef]
- Sun, S.; Dong, H.; Yan, T.; Li, J.; Liu, B.; Shao, P.; Li, J.; Liang, C. Role of TSP-1 as prognostic marker in various cancers: A systematic review and meta-analysis. BMC Med. Genet. 2020, 21, 139. [Google Scholar] [CrossRef]
- Kotlyarov, A.; Neininger, A.; Schubert, C.; Eckert, R.; Birchmeier, C.; Volk, H.D.; Gaestel, M. MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nat. Cell Biol. 1999, 1, 94–97. [Google Scholar] [CrossRef]
- Ter Haar, E.; Prabhakar, P.; Liu, X.; Lepre, C. Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimer. J. Biol. Chem. 2007, 282, 9733–9739. [Google Scholar] [CrossRef] [Green Version]
- White, A.; Pargellis, C.A.; Studts, J.M.; Werneburg, B.G.; Farmer, B.T. 2nd: Molecular basis of MAPK-activated protein kinase 2:p38 assembly. Proc. Natl. Acad. Sci. USA 2007, 104, 6353–6358. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fiore, M.; Forli, S.; Manetti, F. Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts to Lead Small Molecule Inhibitors to Clinical Trials. J. Med. Chem. 2016, 59, 3609–3634. [Google Scholar] [CrossRef] [PubMed]
- Johansen, C.; Vestergaard, C.; Kragballe, K.; Kollias, G.; Gaestel, M.; Iversen, L. MK2 regulates the early stages of skin tumor promotion. Carcinogenesis 2009, 30, 2100–2108. [Google Scholar] [CrossRef] [Green Version]
- Soni, S.; Anand, P.; Padwad, Y.S. MAPKAPK2: The master regulator of RNA-binding proteins modulates transcript stability and tumor progression. J. Exp. Clin. Cancer Res. 2019, 38, 121. [Google Scholar] [CrossRef] [Green Version]
- Dietlein, F.; Kalb, B.; Jokic, M.; Noll, E.M.; Strong, A.; Tharun, L.; Ozretic, L.; Kunstlinger, H.; Kambartel, K.; Randerath, W.J.; et al. A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer. Cell 2015, 162, 146–159. [Google Scholar] [CrossRef] [Green Version]
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Petzelbauer, P. Prevention of Melanoma Extravasation as a New Treatment Option Exemplified by p38/MK2 Inhibition. Int. J. Mol. Sci. 2020, 21, 8344. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218344
Petzelbauer P. Prevention of Melanoma Extravasation as a New Treatment Option Exemplified by p38/MK2 Inhibition. International Journal of Molecular Sciences. 2020; 21(21):8344. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218344
Chicago/Turabian StylePetzelbauer, Peter. 2020. "Prevention of Melanoma Extravasation as a New Treatment Option Exemplified by p38/MK2 Inhibition" International Journal of Molecular Sciences 21, no. 21: 8344. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218344