PERSPECTIVES ON METASTASIS AND SNAKE VENOMS
Main Article Content
Abstract
Metastasis is the major responsible for the death of cancer patients. This malignant feature implies the acquisition of protein machineries that allow cells to migrate, modify the extracellular matrix and form new blood vessels.
Since the discovery of disintegrins as ligands and blockers of integrins, many studies have demonstrated that snake venoms are a source of bioactive molecules with anti-metastatic effect. In this review, snake venom molecules are described as inhibitors of metastasis at different levels, pointing to a need for further research.
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References
Ben-Mabrouk, H., Zouari-Kessentini, R., Montassar, F., Koubaa, Z., Messaadi, E., Guillonneau, X., ElAyeb,
M., Srairi-Abid, N., Luis, J., Micheau, O., & Marrakchi, N. (2016). CC5 and CC8, two homologous
disintegrins from Cerastes cerastes venom, inhibit in vitro and ex vivo angiogenesis.
International Journal of Biological Macromolecules, 86, 670–680.
https://doi.org/10.1016/j.ijbiomac.2016.02.008
Carey, C., Bueno, R., Gutierrez, D., Petro, C., Lucena, S., Sánchez, E., & Soto, J. (2012). Recombinant
rubistatin (r-Rub), an MVD disintegrin, inhibits cell migration and proliferation, and is a strong
apoptotic inducer of the human melanoma cell line SK-Mel-28. Toxicon, 59(2), 241–248.
https://doi.org/10.1016/j.toxicon.2011.12.002
Chen, Y., Chang, Y., Chen, C., Shiu, J., Cheng, C., Huang, C., Chen, J., & Chuang, W. (2020). Structural
Insight into Integrin Recognition and Anticancer Activity of Echistatin. Toxins, 12(11), 709.
https://doi.org/10.3390/toxins12110709
Chin, D., Boyle, G., Kane, A., Theile, D. R., Hayward, N., Parson, P., & Coman, W. (2005). Invasion and
metastasis markers in cancers. British Journal of Plastic Surgery, 58(4), 466–474.
https://doi.org/10.1016/j.bjps.2004.12.025
Chung, K., Kim, S., Han, K., Sohn, Y., Chang, S., Baek, K., Jang, Y., Kim, D., & Kang, I. (2003). Inhibitory
effect of salmosin, a Korean snake venom-derived disintegrin, on the integrin alphav-mediated
proliferation of SK-Mel-2 human melanoma cells. The Journal of Pharmacy and Pharmacology,
(11), 1577–1582. https://doi.org/10.1211/0022357022160
Conlon, G. A., & Murray, G. I. (2019). Recent advances in understanding the roles of matrix
metalloproteinases in tumour invasion and metastasis. The Journal of Pathology, 247(5),
–640. https://doi.org/10.1002/path.5225
Cooper, J., & Giancotti, F. G. (2019). Integrin Signaling in Cancer: Mechanotransduction, Stemness,
PERSPECTIVES ON METASTASIS Gutiérrez-Pajares & Gómez-Betancur
Epithelial Plasticity, and Therapeutic Resistance. Cancer Cell, 35(3), 347–367.
https://doi.org/10.1016/j.ccell.2019.01.007
Corrêa, M. C., Maria, D. A., Moura-da-Silva, A. M., Pizzocaro, K. F., & Ruiz, I. R. G. (2002). Inhibition of
melanoma cells tumorigenicity by the snake venom toxin jararhagin. Toxicon: Official Journal of
the International Society on Toxinology, 40(6), 739–748. https://doi.org/10.1016/s0041-
(01)00275-6
Danen, E. H., Marcinkiewicz, C., Cornelissen, I. M., van Kraats, A. A., Pachter, J. A., Ruiter, D. J.,
Niewiarowski, S., & van Muijen, G. N. (1998). The disintegrin eristostatin interferes with integrin
alpha 4 beta 1 function and with experimental metastasis of human melanoma cells.
Experimental Cell Research, 238(1), 188–196. https://doi.org/10.1006/excr.1997.3821
de Vasconcelos Azevedo, F., Zóia, M., Lopes, D., Gimenes, S., Vecchi, L., Alves, P., Rodrigues, R., Silva, A.
C., Yoneyama, K., Goulart, L., & de Melo Rodrigues, V. (2019). Antitumor and antimetastatic
effects of PLA2-BthTX-II from Bothrops jararacussu venom on human breast cancer cells.
International Journal of Biological Macromolecules, 135, 261–273.
https://doi.org/10.1016/j.ijbiomac.2019.05.164
Della Morte, R., Squillacioti, C., Garbi, C., Derkinderen, P., Belisario, M. A., Girault, J.-A., Di Natale, P.,
Nitsch, L., & Staiano, N. (2000). Echistatin inhibits pp125FAK autophosphorylation, paxillin
phosphorylation and pp125FAK-paxillin interaction in fibronectin-adherent melanoma cells:
Echistatin inhibits paxillin phosphorylation. European Journal of Biochemistry, 267(16),
–5054. https://doi.org/10.1046/j.1432-1327.2000.01561.x
Eble, J., Niland, S., Dennes, A., Schmidt-Hederich, A., Bruckner, P., & Brunner, G. (2002). Rhodocetin
antagonizes stromal tumor invasion in vitro and other α2β1 integrin-mediated cell functions.
Matrix Biology, 21(7), 547–558. https://doi.org/10.1016/S0945-053X(02)00068-9
Fares, J., Fares, M., Khachfe, H., Salhab, H., & Fares, Y. (2020). Molecular principles of metastasis: A
PERSPECTIVES ON METASTASIS Gutiérrez-Pajares & Gómez-Betancur
hallmark of cancer revisited. Signal Transduction and Targeted Therapy, 5(1), 28.
https://doi.org/10.1038/s41392-020-0134-x
Garcia, M. A., Nelson, W. J., & Chavez, N. (2018). Cell–Cell Junctions Organize Structural and Signaling
Networks. Cold Spring Harbor Perspectives in Biology, 10(4), a029181.
https://doi.org/10.1101/cshperspect.a029181
Guimarães, D. de O., Lopes, D., Azevedo, F., Gimenes, S., Silva, M., Achê, D., Gomes, M., Vecchi, L.,
Goulart, L., Yoneyama, K., Rodrigues, R., & Rodrigues, V. (2017). In vitro antitumor and
antiangiogenic effects of Bothropoidin, a metalloproteinase from Bothrops pauloensis snake
venom. International Journal of Biological Macromolecules, 97, 770–777.
https://doi.org/10.1016/j.ijbiomac.2017.01.064
Hamidi, H., & Ivaska, J. (2018). Every step of the way: Integrins in cancer progression and metastasis.
Nature Reviews Cancer, 18(9), 533–548. https://doi.org/10.1038/s41568-018-0038-z
Huang, M., Wu, S., Hu, Q., Wu, H., Wei, S., Xie, H., Sun, K., Li, X., & Fang, L. (2016). Agkihpin, a novel
SVAE may inhibit the migration and invasion of liver cancer cells associated with the inversion of
EMT induced by Wnt/β-catenin signaling inhibition. Biochemical and Biophysical Research
Communications, 479(2), 283–289. https://doi.org/10.1016/j.bbrc.2016.09.060
Jang, Y., Kim, D., Jeon, O., & Kim, D. (2007). Saxatilin Suppresses Tumor-induced Angiogenesis by
Regulating VEGF Expression in NCI-H460 Human Lung Cancer Cells. BMB Reports, 40(3),
–443. https://doi.org/10.5483/BMBRep.2007.40.3.439
Kang, I., Lee, Y., & Kim, D. (1999). A novel disintegrin salmosin inhibits tumor angiogenesis. Cancer
Research, 59(15), 3754–3760.
Kang, Y., & Massagué, J. (2004). Epithelial-Mesenchymal Transitions. Cell, 118(3), 277–279.
https://doi.org/10.1016/j.cell.2004.07.011
Kim, D., Jang, Y., Jeon, O., & Kim, D. (2007). Saxatilin, a Snake Venom Disintegrin, Suppresses TNF-α-
PERSPECTIVES ON METASTASIS Gutiérrez-Pajares & Gómez-Betancur
induced Ovarian Cancer Cell Invasion. BMB Reports, 40(2), 290–294.
https://doi.org/10.5483/BMBRep.2007.40.2.290
Knudsen, K., Tuszynski, G., Huang, T., & Niewiarowski, S. (1988). Trigramin, an RGD-containing peptide
from snake venom, inhibits cell-substratum adhesion of human melanoma cells. Experimental
Cell Research, 179(1), 42–49. https://doi.org/10.1016/0014-4827(88)90346-1
Latinović, Z., Leonardi, A., Petan, T., Žlajpah, M., & Križaj, I. (2017). Disintegrins from the Venom of
Vipera ammodytes ammodytes Efficiently Inhibit Migration of Breast Cancer Cells. Acta Chimica
Slovenica, 555–559. https://doi.org/10.17344/acsi.2016.2924
Li, M.-Z., Wang, J.-J., Yang, S.-B., Li, W.-F., Xiao, L.-B., He, Y.-L., & Song, X.-M. (2017). ZEB2 promotes
tumor metastasis and correlates with poor prognosis of human colorectal cancer. American
Journal of Translational Research, 9(6), 2838–2851.
Li, Y., Fei, H., Lin, Q., Liang, F., You, Y., Li, M., Wu, M., Qu, Y., Li, P., Yuan, Y., Chen, T., & Jiang, H. (2021).
ZEB2 facilitates peritoneal metastasis by regulating the invasiveness and tumorigenesis of
cancer stem-like cells in high-grade serous ovarian cancers. Oncogene, 40(32), 5131–5141.
https://doi.org/10.1038/s41388-021-01913-3
Lucena, S., Castro, R., Lundin, C., Hofstetter, A., Alaniz, A., Suntravat, M., & Sánchez, E. (2015). Inhibition
of pancreatic tumoral cells by snake venom disintegrins. Toxicon: Official Journal of the
International Society on Toxinology, 93, 136–143. https://doi.org/10.1016/j.toxicon.2014.11.228
Lucena, S., Jia, Y., Soto, J. G., Parral, J., Cantu, E., Brannon, J., Lardner, K., Ramos, C., Seoane, A., &
Sánchez, E.(2012). Anti-invasive and anti-adhesive activities of a recombinant disintegrin, r-
viridistatin 2, derived from the Prairie rattlesnake (Crotalus viridis viridis). Toxicon, 60(1), 31–39.
https://doi.org/10.1016/j.toxicon.2012.03.011
Lucena, S., Sánchez, E., & Pérez, J. (2011). Anti-metastatic activity of the recombinant disintegrin, r-
mojastin 1, from the Mohave rattlesnake. Toxicon, 57(5), 794–802.
PERSPECTIVES ON METASTASIS Gutiérrez-Pajares & Gómez-Betancur
https://doi.org/10.1016/j.toxicon.2011.02.014
Marcinkiewicz, C., Calvete, J., Marcinkiewicz, M., Raida, M., Vijay-Kumar, S., Huang, Z., Lobb, R., &
Niewiarowski, S. (1999). EC3, a novel heterodimeric disintegrin from Echis carinatus venom,
inhibits alpha4 and alpha5 integrins in an RGD-independent manner. The Journal of Biological
Chemistry, 274(18), 12468–12473. https://doi.org/10.1074/jbc.274.18.12468
Marcinkiewicz, C., Weinreb, P., Calvete, J. J., Kisiel, D., Mousa, S. A., Tuszynski, G., & Lobb, R. (2003).
Obtustatin: A potent selective inhibitor of alpha1beta1 integrin in vitro and angiogenesis in vivo.
Cancer Research, 63(9), 2020–2023.
Markland, F., Shieh, K., Zhou, Q., Golubkov, V., Sherwin, R., Richters, V., & Sposto, R. (2001). A Novel
Snake Venom Disintegrin That Inhibits Human Ovarian Cancer Dissemination and Angiogenesis
in an Orthotopic Nude Mouse Model. Pathophysiology of Haemostasis and Thrombosis, 31(3–6),
–191. https://doi.org/10.1159/000048062
Mittal, V. (2018). Epithelial Mesenchymal Transition in Tumor Metastasis. Annual Review of Pathology:
Mechanisms of Disease, 13(1), 395–412. https://doi.org/10.1146/annurev-pathol-020117-
Montealegre-Sánchez, L., Gimenes, S., Lopes, D. , Teixeira, S. C., Solano-Redondo, L., de Melo Rodríguez,
V., & Jiménez-Charris, E. (2019). Antitumoral Potential of Lansbermin-I, a Novel Disintegrin from
Porthidium lansbergii lansbergii Venom on Breast Cancer Cells. Current Topics in Medicinal
Chemistry, 19(22), 2069–2078. https://doi.org/10.2174/1568026619666190806151401
Montenegro, C., Casali, B., Lino, R., Pachane, B., Santos, P., Horwitz, A., Selistre-de-Araujo, H., & Lamers,
M.(2017). Inhibition of αvβ3 integrin induces loss of cell directionality of oral squamous
carcinoma cells (OSCC). PLOS ONE, 12(4), e0176226.
https://doi.org/10.1371/journal.pone.0176226
Moritz, M., Casali, B., Stotzer, U., Karina dos Santos, P., & Selistre-de-Araujo, H. (2022). Alternagin-C, an
PERSPECTIVES ON METASTASIS Gutiérrez-Pajares & Gómez-Betancur
alpha2beta1 integrin ligand, attenuates collagen-based adhesion, stimulating the metastasis
suppressor 1 expression in triple-negative breast tumor cells. Toxicon, 210, 1–10.
https://doi.org/10.1016/j.toxicon.2022.02.001
Morris, V., Schmidt, E., Koop, S., MacDonald, I., Grattan, M., Khokha, R., McLane, M., Niewiarowski, S.,
Chambers, A., & Groom, A. (1995). Effects of the disintegrin eristostatin on individual steps of
hematogenous metastasis. Experimental Cell Research, 219(2), 571–578.
https://doi.org/10.1006/excr.1995.1266
Nishida, N., Yano, H., Nishida, T., Kamura, T., & Kojiro, M. (2006). Angiogenesis in cancer. Vascular
Health and Risk Management, 2(3), 213–219. https://doi.org/10.2147/vhrm.2006.2.3.213
Oshikawa, K., & Terada, S. (1999). Ussuristatin 2, a novel KGD-bearing disintegrin from Agkistrodon
ussuriensis venom. Journal of Biochemistry, 125(1), 31–35.
https://doi.org/10.1093/oxfordjournals.jbchem.a022264
Patteson, A., Vahabikashi, A., Goldman, R., & Janmey, P. (2020). Mechanical and Non‐Mechanical
Functions of Filamentous and Non‐Filamentous Vimentin. BioEssays, 42(11), 2000078.
https://doi.org/10.1002/bies.202000078
Ramos, O., Kauskot, A., Cominetti, M., Bechyne, I., Salla Pontes, C., Chareyre, F., Manent, J., Vassy, R.,
Giovannini, M., Legrand, C., Selistre-de-Araujo, H., Crépin, M., & Bonnefoy, A. (2008). A novel
αvβ3-blocking disintegrin containing the RGD motive, DisBa-01, inhibits bFGF-induced
angiogenesis and melanoma metastasis. Clinical & Experimental Metastasis, 25(1), 53–64.
https://doi.org/10.1007/s10585-007-9101-y
Ramovs, V., Krotenberg Garcia, A., Kreft, M., & Sonnenberg, A. (2021). Integrin α3β1 Is a Key Regulator
of Several Protumorigenic Pathways during Skin Carcinogenesis. Journal of Investigative
Dermatology, 141(4), 732-741.e6. https://doi.org/10.1016/j.jid.2020.07.024
Ritter, M., Zhou, Q., & Markland, F. (2000). Contortrostatin, a snake venom disintegrin, induces
PERSPECTIVES ON METASTASIS Gutiérrez-Pajares & Gómez-Betancur
alphavbeta3-mediated tyrosine phosphorylation of CAS and FAK in tumor cells. Journal of
Cellular Biochemistry, 79(1), 28–37. PMID: 10906753.
Saentaweesuk, W., Araki, N., Vaeteewoottacharn, K., Silsirivanit, A., Seubwai, W., Talabnin, C., Muisuk,
K., Sripa, B., Wongkham, S., Okada, S., & Wongkham, C. (2018). Activation of Vimentin Is Critical
to Promote a Metastatic Potential of Cholangiocarcinoma Cells. Oncology Research Featuring
Preclinical and Clinical Cancer Therapeutics, 26(4), 605–616.
https://doi.org/10.3727/096504017X15009778205068
Sánchez, E., Rodríguez-Acosta, A., Palomar, R., Lucena, S., Bashir, S., Soto, J., & Pérez, J. (2009).
Colombistatin: A disintegrin isolated from the venom of the South American snake (Bothrops
colombiensis) that effectively inhibits platelet aggregation and SK-Mel-28 cell adhesion. Archives
of Toxicology, 83(3), 271–279. https://doi.org/10.1007/s00204-008-0358-y
Sarray, S., Berthet, V., Calvete, J. J., Secchi, J., Marvaldi, J., El-Ayeb, M., Marrakchi, N., & Luis, J. (2004).
Lebectin, a novel C-type lectin from Macrovipera lebetina venom, inhibits integrin-mediated
adhesion, migration and invasion of human tumour cells. Laboratory Investigation; a Journal of
Technical Methods and Pathology, 84(5), 573–581. https://doi.org/10.1038/labinvest.3700088
Saviola, A., Burns, P., Mukherjee, A., & Mackessy, S. (2016). The disintegrin tzabcanin inhibits adhesion
and migration in melanoma and lung cancer cells. International Journal of Biological
Macromolecules, 88, 457–464. https://doi.org/10.1016/j.ijbiomac.2016.04.008
Schmitmeier, S., Markland, F., & Chen, T. (2000). Anti-invasive effect of contortrostatin, a snake venom
disintegrin, and TNF-alpha on malignant glioma cells. Anticancer Research, 20(6B), 4227–4233.
Sheu, J., Lin, C., Peng, H., & Huang, T. (1994). Triflavin, an Arg-Gly-Asp-containing peptide, inhibits
human cervical carcinoma (HeLa) cell-substratum adhesion through an RGD-dependent
mechanism. Peptides, 15(8), 1391–1398. https://doi.org/10.1016/0196-9781(94)90114-7
Soszka, T., Knudsen, K. A., Beviglia, L., Rossi, C., Poggi, A., & Niewiarowski, S. (1991). Inhibition of murine
PERSPECTIVES ON METASTASIS Gutiérrez-Pajares & Gómez-Betancur
melanoma cell-matrix adhesion and experimental metastasis by albolabrin, an RGD-containing
peptide isolated from the venom of Trimeresurus albolabris. Experimental Cell Research, 196(1),
–12. https://doi.org/10.1016/0014-4827(91)90449-5
Staiano, N., Villani, G., Di Martino, E., Squillacioti, C., Vuotto, P., & Di Natale, P. (1995). Echistatin inhibits
the adhesion of murine melanoma cells to extracellular matrix components. Biochemistry and
Molecular Biology International, 35(1), 11–19.
Staniszewska, I., Walsh, E., Rothman, V., Gaathon, A., Tuszynski, G., Calvete, J., Lazarovici, P., &
Marcinkiewicz, C. (2009). Effect of VP12 and viperistatin on inhibition of collagen receptors:
Dependent melanoma metastasis. Cancer Biology & Therapy, 8(15), 1507–1516.
https://doi.org/10.4161/cbt.8.15.8999
Swenson, S., Costa, F., Minea, R., Sherwin, R., Ernst, W., Fujii, G., Yang, D., & Markland, F. (2004).
Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast
cancer progression. Molecular Cancer Therapeutics, 3(4), 499–511.
Takeshima, H., & Ushijima, T. (2019). Accumulation of genetic and epigenetic alterations in normal cells
and cancer risk. Npj Precision Oncology, 3(1), 7. https://doi.org/10.1038/s41698-019-0079-0
Tang, N., Xie, Q., Wang, X., Li, X., Chen, Y., Lin, X., & Lin, J. (2011). Inhibition of invasion and metastasis of
MHCC97H cells by expression of snake venom cystatin through reduction of proteinases activity
and epithelial-mesenchymal transition. Archives of Pharmacal Research, 34(5), 781–789.
https://doi.org/10.1007/s12272-011-0512-6
Trikha, M., De Clerck, Y., & Markland, F. (1994). Contortrostatin, a snake venom disintegrin, inhibits beta
integrin-mediated human metastatic melanoma cell adhesion and blocks experimental
metastasis. Cancer Research, 54(18), 4993–4998.
Tsai, P., Fu, Y., Chang, L., & Lin, S. (2016). Taiwan cobra cardiotoxin III suppresses EGF/EGFR-mediated
epithelial-to-mesenchymal transition and invasion of human breast cancer MDA-MB-231 cells.
PERSPECTIVES ON METASTASIS Gutiérrez-Pajares & Gómez-Betancur
Toxicon, 111, 108–120. https://doi.org/10.1016/j.toxicon.2016.01.051
Wang, Y., Shi, J., Chai, K., Ying, X., & Zhou, B. (2013). The Role of Snail in EMT and Tumorigenesis. Current
Cancer Drug Targets, 13(9), 963–972. https://doi.org/10.2174/15680096113136660102
Wels, C., Joshi, S., Koefinger, P., Bergler, H., & Schaider, H. (2011). Transcriptional Activation of ZEB1 by
Slug Leads to Cooperative Regulation of the Epithelial–Mesenchymal Transition-Like Phenotype
in Melanoma. Journal of Investigative Dermatology, 131(9), 1877–1885.
https://doi.org/10.1038/jid.2011.142
Xie, Q., Tang, N., Wan, R., Qi, Y., Lin, X., & Lin, J. (2011). Recombinant snake venom cystatin inhibits the
growth, invasion and metastasis of B16F10 cells and MHCC97H cells in vitro and in vivo. Toxicon,
(5), 704–711. https://doi.org/10.1016/j.toxicon.2011.02.002
Yamaguchi, H., & Condeelis, J. (2007). Regulation of the actin cytoskeleton in cancer cell migration and
invasion. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1773(5), 642–652.
https://doi.org/10.1016/j.bbamcr.2006.07.001
Yang, Y., Sun, M., Wang, L., & Jiao, B. (2013). HIFs, angiogenesis, and cancer. Journal of Cellular
Biochemistry, 114(5), 967–974. https://doi.org/10.1002/jcb.24438
Yeh, C., Peng, H. Yang, R., & Huang, T. (2001). Rhodostomin, A Snake Venom Disintegrin, Inhibits
Angiogenesis Elicited by Basic Fibroblast Growth Factor and Suppresses Tumor Growth by A
Selective α v β 3 Blockade of Endothelial Cells. Molecular Pharmacology, 59(5), 1333–1342.
https://doi.org/10.1124/mol.59.5.1333
Zhang, Q., Lin, F., Huang, J., & Xiong, C. (2022). Mechanical transmission enables EMT cancer cells to
drive epithelial cancer cell migration to guide tumor spheroid disaggregation. Science China Life
Sciences, 65(10), 2031–2049. https://doi.org/10.1007/s11427-021-2054-3
Zhou, Q., Nakada, M., Brooks, P., Swenson, S., Ritter, M. R., Argounova, S., Arnold, C., & Markland, F. S.
(2000). Contortrostatin, a Homodimeric Disintegrin, Binds to Integrin αvβ5. Biochemical and
PERSPECTIVES ON METASTASIS Gutiérrez-Pajares & Gómez-Betancur
Biophysical Research Communications, 267(1), 350–355.
https://doi.org/10.1006/bbrc.1999.1965
Zhou, Q., Sherwin, R., Parrish, C., Richters, V., Groshen, S., Tsao-Wei, D., & Markland, F. (2000).
Contortrostatin, a dimeric disintegrin from contortrix contortrix, inhibits breast cancer
progression. Breast Cancer Research and Treatment, 61(3), 249–259.
https://doi.org/10.1023/A:1006457903545
Zitka, O., Kukacka, J., Krizkov, S., Huska, D., Adam, V., Masarik, M., Prusa, R., & Kizek, R. (2010). Matrix
Metalloproteinases. Current Medicinal Chemistry, 17(31), 3751–3768.