Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Perspective

Insights into Melanoma Fibroblast Populations and Therapeutic Strategy Perspectives: Friends or Foes?

Author(s): Angelica Avagliano* and Alessandro Arcucci

Volume 29, Issue 40, 2022

Published on: 15 August, 2022

Page: [6159 - 6168] Pages: 10

DOI: 10.2174/0929867329666220620124138

Abstract

Cutaneous melanoma (CM) is an aggressive and highly metastatic solid tumor associated with drug resistance. Before 2011, despite therapies based on cytokines or molecules inhibiting DNA synthesis, metastatic melanoma led to patient death within 18 months from diagnosis. However, recent studies on bidirectional interactions between melanoma cells and tumor microenvironment (TME) have had a significant impact on the development of new therapeutic strategies represented by targeted therapy and immunotherapy. In particular, the heterogeneous stromal fibroblast populations, including fibroblasts, fibroblast aggregates, myofibroblasts, and melanoma associated fibroblasts (MAFs), represent the most abundant cell population of TME and regulate cancer growth differently. Therefore, in this perspective article, we have highlighted the different impacts of fibroblast populations on cancer development and growth. In particular, we focused on the role of MAFs in sustaining melanoma cell survival, proliferation, migration and invasion, drug resistance, and immunoregulation. The important role of constitutively activated MAFs in promoting CM growth and immunoediting makes this cell type a promising target for cancer therapy.

Keywords: Cutaneous melanoma, melanoma microenvironment, fibroblast populations, normal fibroblasts, melanoma associated fibroblasts, therapeutic perspectives.

« Previous Next »
[1]
Romano, V.; Belviso, I.; Venuta, A.; Ruocco, M.R.; Masone, S.; Aliotta, F.; Fiume, G.; Montagnani, S.; Avagliano, A.; Arcucci, A. Influence of tumor microenvironment and fibroblast population plasticity on melanoma growth, therapy resistance and immunoescape. Int. J. Mol. Sci., 2021, 22(10), 5283.
[http://dx.doi.org/10.3390/ijms22105283] [PMID: 34067929]
[2]
Avagliano, A.; Fiume, G.; Pelagalli, A.; Sanità, G.; Ruocco, M.R.; Montagnani, S.; Arcucci, A. Metabolic plasticity of melanoma cells and their crosstalk with tumor microenvironment. Front. Oncol., 2020, 10, 722.
[http://dx.doi.org/10.3389/fonc.2020.00722] [PMID: 32528879]
[3]
Zhou, L.; Yang, K.; Randall Wickett, R.; Zhang, Y. Dermal fibroblasts induce cell cycle arrest and block epithelial-mesenchymal transition to inhibit the early stage melanoma development. Cancer Med., 2016, 5(7), 1566-1579.
[http://dx.doi.org/10.1002/cam4.707] [PMID: 27061029]
[4]
Cornil, I.; Theodorescu, D.; Man, S.; Herlyn, M.; Jambrosic, J.; Kerbel, R.S. Fibroblast cell interactions with human melanoma cells affect tumor cell growth as a function of tumor progression. Proc. Natl. Acad. Sci. USA, 1991, 88(14), 6028-6032.
[http://dx.doi.org/10.1073/pnas.88.14.6028] [PMID: 2068080]
[5]
Avagliano, A.; Ruocco, M.R.; Nasso, R.; Aliotta, F.; Sanità, G.; Iaccarino, A.; Bellevicine, C.; Calì, G.; Fiume, G.; Masone, S.; Masullo, M.; Montagnani, S.; Arcucci, A. Development of a stromal microenvironment experimental model containing proto-myofibroblast like cells and analysis of its crosstalk with melanoma cells: A new tool to potentiate and stabilize tumor suppressor phenotype of dermal myofibroblasts. Cells, 2019, 8(11), E1435.
[http://dx.doi.org/10.3390/cells8111435] [PMID: 31739477]
[6]
Cheng, N.; Bhowmick, N.A.; Chytil, A.; Gorksa, A.E.; Brown, K.A.; Muraoka, R.; Arteaga, C.L.; Neilson, E.G.; Hayward, S.W.; Moses, H.L. Loss of TGF-β type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-α-, MSP- and HGF-mediated signaling networks. Oncogene, 2005, 24(32), 5053-5068.
[http://dx.doi.org/10.1038/sj.onc.1208685] [PMID: 15856015]
[7]
Rappl, G.; Kapsokefalou, A.; Heuser, C.; Rössler, M.; Ugurel, S.; Tilgen, W.; Reinhold, U.; Abken, H. Dermal fibroblasts sustain proliferation of activated T cells via membrane-bound interleukin-15 upon long-term stimulation with tumor necrosis factor-α. J. Invest. Dermatol., 2001, 116(1), 102-109.
[http://dx.doi.org/10.1046/j.1523-1747.2001.00239.x] [PMID: 11168804]
[8]
Zhou, L.; Yang, K.; Andl, T.; Wickett, R.R.; Zhang, Y. Perspective of targeting cancer-associated fibroblasts in melanoma. J. Cancer, 2015, 6(8), 717-726.
[http://dx.doi.org/10.7150/jca.10865] [PMID: 26185533]
[9]
Kaur, A.; Webster, M.R.; Marchbank, K.; Behera, R.; Ndoye, A.; Kugel, C.H., III; Dang, V.M.; Appleton, J.; O’Connell, M.P.; Cheng, P.; Valiga, A.A.; Morissette, R.; McDonnell, N.B.; Ferrucci, L.; Kossenkov, A.V.; Meeth, K.; Tang, H.Y.; Yin, X.; Wood, W.H., III; Lehrmann, E.; Becker, K.G.; Flaherty, K.T.; Frederick, D.T.; Wargo, J.A.; Cooper, Z.A.; Tetzlaff, M.T.; Hudgens, C.; Aird, K.M.; Zhang, R.; Xu, X.; Liu, Q.; Bartlett, E.; Karakousis, G.; Eroglu, Z.; Lo, R.S.; Chan, M.; Menzies, A.M.; Long, G.V.; Johnson, D.B.; Sosman, J.; Schilling, B.; Schadendorf, D.; Speicher, D.W.; Bosenberg, M.; Ribas, A.; Weeraratna, A.T. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature, 2016, 532(7598), 250-254.
[http://dx.doi.org/10.1038/nature17392] [PMID: 27042933]
[10]
Guan, X.; LaPak, K.M.; Hennessey, R.C.; Yu, C.Y.; Shakya, R.; Zhang, J.; Burd, C.E. Stromal senescence by prolonged CDK4/6 inhibition potentiates tumor growth. Mol. Cancer Res., 2017, 15(3), 237-249.
[http://dx.doi.org/10.1158/1541-7786.MCR-16-0319] [PMID: 28039358]
[11]
Alicea, G.M.; Rebecca, V.W.; Goldman, A.R.; Fane, M.E.; Douglass, S.M.; Behera, R.; Webster, M.R.; Kugel, C.H., III; Ecker, B.L.; Caino, M.C.; Kossenkov, A.V.; Tang, H.Y.; Frederick, D.T.; Flaherty, K.T.; Xu, X.; Liu, Q.; Gabrilovich, D.I.; Herlyn, M.; Blair, I.A.; Schug, Z.T.; Speicher, D.W.; Weeraratna, A.T. Changes in aged fibroblast lipid metabolism induce age-dependent melanoma cell resistance to targeted therapy via the fatty acid transporter FATP2. Cancer Discov., 2020, 10(9), 1282-1295.
[http://dx.doi.org/10.1158/2159-8290.CD-20-0329] [PMID: 32499221]
[12]
Dror, S.; Sander, L.; Schwartz, H.; Sheinboim, D.; Barzilai, A.; Dishon, Y.; Apcher, S.; Golan, T.; Greenberger, S.; Barshack, I.; Malcov, H.; Zilberberg, A.; Levin, L.; Nessling, M.; Friedmann, Y.; Igras, V.; Barzilay, O.; Vaknine, H.; Brenner, R.; Zinger, A.; Schroeder, A.; Gonen, P.; Khaled, M.; Erez, N.; Hoheisel, J.D.; Levy, C. Melanoma miRNA trafficking controls tumour primary niche formation. Nat. Cell Biol., 2016, 18(9), 1006-1017.
[http://dx.doi.org/10.1038/ncb3399] [PMID: 27548915]
[13]
Granato, G.; Ruocco, M.R.; Iaccarino, A.; Masone, S.; Calì, G.; Avagliano, A.; Russo, V.; Bellevicine, C.; Di Spigna, G.; Fiume, G.; Montagnani, S.; Arcucci, A. Generation and analysis of spheroids from human primary skin myofibroblasts: An experimental system to study myofibroblasts deactivation. Cell Death Discov., 2017, 3, 17038.
[http://dx.doi.org/10.1038/cddiscovery.2017.38] [PMID: 28725488]
[14]
Hodorogea, A.; Calinescu, A.; Antohe, M.; Balaban, M.; Nedelcu, R.I.; Turcu, G.; Ion, D.A.; Badarau, I.A.; Popescu, C.M.; Popescu, R.; Popp, C.; Cioplea, M.; Nichita, L.; Hulea, I.; Brinzea, A. Epithelial-mesenchymal transition in skin cancers: A review. Anal. Cell. Pathol. (Amst.), 2019, 2019, 3851576.
[http://dx.doi.org/10.1155/2019/3851576] [PMID: 31934531]
[15]
Koefinger, P.; Wels, C.; Joshi, S.; Damm, S.; Steinbauer, E.; Beham-Schmid, C.; Frank, S.; Bergler, H.; Schaider, H. The cadherin switch in melanoma instigated by HGF is mediated through epithelial-mesenchymal transition regulators. Pigment Cell Melanoma Res., 2011, 24(2), 382-385.
[http://dx.doi.org/10.1111/j.1755-148X.2010.00807.x] [PMID: 21091638]
[16]
Yang, X.; Lin, Y.; Shi, Y.; Li, B.; Liu, W.; Yin, W.; Dang, Y.; Chu, Y.; Fan, J.; He, R. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling. Cancer Res., 2016, 76(14), 4124-4135.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-2973] [PMID: 27216177]
[17]
Flavell, R.A.; Sanjabi, S.; Wrzesinski, S.H.; Licona-Limón, P. The polarization of immune cells in the tumour environment by TGFbeta. Nat. Rev. Immunol., 2010, 10(8), 554-567.
[http://dx.doi.org/10.1038/nri2808] [PMID: 20616810]
[18]
Cho, H.; Seo, Y.; Loke, K.M.; Kim, S.W.; Oh, S.M.; Kim, J.H.; Soh, J.; Kim, H.S.; Lee, H.; Kim, J.; Min, J.J.; Jung, D.W.; Williams, D.R. Cancer-stimulated CAFs enhance monocyte differentiation and protumoral TAM activation via IL6 and GM-CSF Secretion. Clin. Cancer Res., 2018, 24(21), 5407-5421.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-0125] [PMID: 29959142]
[19]
Nwani, N.G.; Deguiz, M.L.; Jimenez, B.; Vinokour, E.; Dubrovskyi, O.; Ugolkov, A.; Mazar, A.P.; Volpert, O.V. Melanoma cells block pedf production in fibroblasts to induce the tumor-promoting phenotype of cancer-associated fibroblasts. Cancer Res., 2016, 76(8), 2265-2276.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-2468] [PMID: 26921338]
[20]
Yin, M.; Soikkeli, J.; Jahkola, T.; Virolainen, S.; Saksela, O.; Hölttä, E. TGF-β signaling, activated stromal fibroblasts, and cysteine cathepsins B and L drive the invasive growth of human melanoma cells. Am. J. Pathol., 2012, 181(6), 2202-2216.
[http://dx.doi.org/10.1016/j.ajpath.2012.08.027] [PMID: 23063511]
[21]
Hutchenreuther, J.; Vincent, K.M.; Carter, D.E.; Postovit, L.M.; Leask, A. CCN2 expression by tumor stroma is required for melanoma metastasis. J. Invest. Dermatol., 2015, 135(11), 2805-2813.
[http://dx.doi.org/10.1038/jid.2015.279] [PMID: 26168233]
[22]
Artavanis-Tsakonas, S.; Rand, M.D.; Lake, R.J. Notch signaling: Cell fate control and signal integration in development. Science, 1999, 284(5415), 770-776.
[http://dx.doi.org/10.1126/science.284.5415.770] [PMID: 10221902]
[23]
Shao, H.; Huang, Q.; Liu, Z.J. Targeting notch signaling for cancer therapeutic intervention. Adv. Pharmacol., 2012, 65, 191-234.
[http://dx.doi.org/10.1016/B978-0-12-397927-8.00007-5] [PMID: 22959027]
[24]
Liu, Z.J.; Li, Y.; Tan, Y.; Xiao, M.; Zhang, J.; Radtke, F.; Velazquez, O.C. Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1. PLoS One, 2012, 7(6), e38811.
[http://dx.doi.org/10.1371/journal.pone.0038811] [PMID: 22715413]
[25]
Shao, H.; Moller, M.; Cai, L.; Prokupets, R.; Yang, C.; Costa, C.; Yu, K.; Le, N.; Liu, Z.J. Converting melanoma-associated fibroblasts into a tumor-suppressive phenotype by increasing intracellular Notch1 pathway activity. PLoS One, 2021, 16(3), e0248260.
[http://dx.doi.org/10.1371/journal.pone.0248260] [PMID: 33705467]
[26]
Zhou, L.; Yang, K.; Wickett, R.R.; Kadekaro, A.L.; Zhang, Y. Targeted deactivation of cancer-associated fibroblasts by β-catenin ablation suppresses melanoma growth. Tumour Biol., 2016, 37(10), 14235-14248.
[http://dx.doi.org/10.1007/s13277-016-5293-6] [PMID: 27571738]
[27]
Zhao, F.; Evans, K.; Xiao, C.; DeVito, N.; Theivanthiran, B.; Holtzhausen, A.; Siska, P.J.; Blobe, G.C.; Hanks, B.A. Stromal fibroblasts mediate anti-pd-1 resistance via mmp-9 and dictate tgfβ inhibitor sequencing in melanoma. Cancer Immunol. Res., 2018, 6(12), 1459-1471.
[http://dx.doi.org/10.1158/2326-6066.CIR-18-0086] [PMID: 30209062]
[28]
Ohshio, Y.; Teramoto, K.; Hanaoka, J.; Tezuka, N.; Itoh, Y.; Asai, T.; Daigo, Y.; Ogasawara, K. Cancer-associated fibroblast-targeted strategy enhances antitumor immune responses in dendritic cell-based vaccine. Cancer Sci., 2015, 106(2), 134-142.
[http://dx.doi.org/10.1111/cas.12584] [PMID: 25483888]
[29]
Wollin, L.; Distler, J.H.W.; Redente, E.F.; Riches, D.W.H.; Stowasser, S.; Schlenker-Herceg, R.; Maher, T.M.; Kolb, M. Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases. Eur. Respir. J., 2019, 54(3), 1900161.
[http://dx.doi.org/10.1183/13993003.00161-2019] [PMID: 31285305]
[30]
Kato, R.; Haratani, K.; Hayashi, H.; Sakai, K.; Sakai, H.; Kawakami, H.; Tanaka, K.; Takeda, M.; Yonesaka, K.; Nishio, K.; Nakagawa, K. Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: Potential role of cancer-associated fibroblasts. Br. J. Cancer, 2021, 124(5), 914-924.
[http://dx.doi.org/10.1038/s41416-020-01201-z] [PMID: 33299131]
[31]
Waldhauer, I.; Gonzalez-Nicolini, V.; Freimoser-Grundschober, A.; Nayak, T.K.; Fahrni, L.; Hosse, R.J.; Gerrits, D.; Geven, E.J.W.; Sam, J.; Lang, S.; Bommer, E.; Steinhart, V.; Husar, E.; Colombetti, S.; Van Puijenbroek, E.; Neubauer, M.; Cline, J.M.; Garg, P.K.; Dugan, G.; Cavallo, F.; Acuna, G.; Charo, J.; Teichgräber, V.; Evers, S.; Boerman, O.C.; Bacac, M.; Moessner, E.; Umaña, P.; Klein, C. Simlukafusp alfa (FAP-IL2v) immunocytokine is a versatile combination partner for cancer immunotherapy. MAbs, 2021, 13(1), 1913791.
[http://dx.doi.org/10.1080/19420862.2021.1913791] [PMID: 33974508]
[32]
Érsek, B.; Silló, P.; Cakir, U.; Molnár, V.; Bencsik, A.; Mayer, B.; Mezey, E.; Kárpáti, S.; Pós, Z.; Németh, K. Melanoma-associated fibroblasts impair CD8+ T cell function and modify expression of immune checkpoint regulators via increased arginase activity. Cell. Mol. Life Sci., 2021, 78(2), 661-673.
[http://dx.doi.org/10.1007/s00018-020-03517-8] [PMID: 32328671]
[33]
Zhang, Y.; Ertl, H.C.J. Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors. Oncotarget, 2016, 7(17), 23282-23299.
[http://dx.doi.org/10.18632/oncotarget.7818] [PMID: 26943036]
[34]
Soerensen, M.M.; Ros, W.; Rodriguez-Ruiz, M.E.; Robbrecht, D.; Rohrberg, K.S.; Martin-Liberal, J.; Lassen, U.N.; Bermejo, I.M.; Lolkema, M.P.; Tabernero, J. Safety, PK/PD, and anti-tumor activity of RO6874281, an engineered variant of interleukin-2 (IL-2v) targeted to tumor-associated fibroblasts via binding to fibroblast activation protein (FAP) 2018, 36, 15155.
[http://dx.doi.org/10.1200/JCO.2018.36.15_suppl.e15155]
[35]
Albano, F.; Vecchio, E.; Renna, M.; Iaccino, E.; Mimmi, S.; Caiazza, C.; Arcucci, A.; Avagliano, A.; Pagliara, V.; Donato, G.; Palmieri, C.; Mallardo, M.; Quinto, I.; Fiume, G. Insights into thymus development and viral thymic infections. Viruses, 2019, 11(9), E836.
[http://dx.doi.org/10.3390/v11090836] [PMID: 31505755]
[36]
Sunami, Y.; Böker, V.; Kleeff, J. Targeting and reprograming cancer-associated fibroblasts and the tumor microenvironment in pancreatic cancer. Cancers (Basel), 2021, 13(4), 1-14.
[http://dx.doi.org/10.3390/cancers13040697] [PMID: 33572223]
[37]
Hu, S.; Ma, J.; Su, C.; Chen, Y.; Shu, Y.; Qi, Z.; Zhang, B.; Shi, G.; Zhang, Y.; Zhang, Y.; Huang, A.; Kuang, Y.; Cheng, P. Engineered exosome-like nanovesicles suppress tumor growth by reprogramming tumor microenvironment and promoting tumor ferroptosis. Acta Biomater., 2021, 135, 567-581.
[http://dx.doi.org/10.1016/j.actbio.2021.09.003] [PMID: 34506976]
[38]
Li, W.; Little, N.; Park, J.; Foster, C.A.; Chen, J.; Lu, J. Tumor-associated fibroblast-targeting nanoparticles for enhancing solid tumor therapy: Progress and challenges. Mol. Pharm., 2021, 18(8), 2889-2905.
[http://dx.doi.org/10.1021/acs.molpharmaceut.1c00455] [PMID: 34260250]
[39]
Yunna, C.; Mengru, H.; Fengling, W.; Lei, W.; Weidong, C. Emerging strategies against tumor-associated fibroblast for improved the penetration of nanoparticle into desmoplastic tumor. Eur. J. Pharm. Biopharm., 2021, 165, 75-83.
[http://dx.doi.org/10.1016/j.ejpb.2021.05.007] [PMID: 33991610]
[40]
Stylianopoulos, T.; Martin, J.D.; Chauhan, V.P.; Jain, S.R.; Diop-Frimpong, B.; Bardeesy, N.; Smith, B.L.; Ferrone, C.R.; Hornicek, F.J.; Boucher, Y.; Munn, L.L.; Jain, R.K. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. Proc. Natl. Acad. Sci. USA, 2012, 109(38), 15101-15108.
[http://dx.doi.org/10.1073/pnas.1213353109] [PMID: 22932871]
[41]
Nishihara, H. Human pathological basis of blood vessels and stromal tissue for nanotechnology. Adv. Drug Deliv. Rev., 2014, 74, 19-27.
[http://dx.doi.org/10.1016/j.addr.2014.01.005] [PMID: 24462455]
[42]
Liu, M.; Song, W.; Huang, L. Drug delivery systems targeting tumor-associated fibroblasts for cancer immunotherapy. Cancer Lett., 2019, 448, 31-39.
[http://dx.doi.org/10.1016/j.canlet.2019.01.032] [PMID: 30731107]
[43]
Liu, Q.; Chen, F.; Hou, L.; Shen, L.; Zhang, X.; Wang, D.; Huang, L. Nanocarrier-mediated chemo-immunotherapy arrested cancer progression and induced tumor dormancy in desmoplastic melanoma. ACS Nano, 2018, 12(8), 7812-7825.
[http://dx.doi.org/10.1021/acsnano.8b01890] [PMID: 30016071]
[44]
Hou, L.; Liu, Q.; Shen, L.; Liu, Y.; Zhang, X.; Chen, F.; Huang, L. Nano-delivery of fraxinellone remodels tumor microenvironment and facilitates therapeutic vaccination in desmoplastic melanoma. Theranostics, 2018, 8(14), 3781-3796.
[http://dx.doi.org/10.7150/thno.24821] [PMID: 30083259]
[45]
Huo, M.; Zhao, Y.; Satterlee, A.B.; Wang, Y.; Xu, Y.; Huang, L. Tumor-targeted delivery of sunitinib base enhances vaccine therapy for advanced melanoma by remodeling the tumor microenvironment. J. Control. Release, 2017, 245, 81-94.
[http://dx.doi.org/10.1016/j.jconrel.2016.11.013] [PMID: 27863995]
[46]
Zhao, Y.; Huo, M.; Xu, Z.; Wang, Y.; Huang, L. Nanoparticle delivery of CDDO-Me remodels the tumor microenvironment and enhances vaccine therapy for melanoma. Biomaterials, 2015, 68, 54-66.
[http://dx.doi.org/10.1016/j.biomaterials.2015.07.053] [PMID: 26264646]

Rights & Permissions Print Cite
Article Metrics
45
3
World Chagas Disease
© 2024 Bentham Science Publishers | Privacy Policy