Targeting Tumor Microenvironment for Cancer Therapy
Abstract
:1. Introduction
2. Targeting the Tumor Microenvironment
2.1. Targeting the Extracellular Matrix
2.2. Targeting Hypoxia and Acidosis
2.3. Avoiding Neovascularization—Targeting Endothelial Cells and Pericytes
2.4. Targeting Immune System
2.4.1. Inhibiting Macrophages Recruitment and Differentiation
2.4.2. Targeting Chronic Inflammation
2.4.3. Activating Anti-Tumoral Activity of Immune System
2.5. Targeting Cancer-Associated Fibroblasts
2.6. Targeting Exosomes
3. The Case of Combined Therapies
4. Nanomedicines
5. Models for the Study of TME
6. Conclusions and Outlook
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ANGPT | Angiopoietin |
ARG1 | Arginase 1 |
CAFs | Cancer-associated fibroblasts |
CSC | Cancer stem cell |
CSF | Colony stimulating factor |
CTLA-4 | Cytotoxic T-lymphocyte-associated protein 4 |
ECM | Extracellular matrix |
EGF | Epidermal growth factor |
EMT | Epithelial-to-mesenchymal transition |
EPR | Enhanced permeability and retention |
FAP | Fibroblast activation protein |
FGF | Fibroblast growth factor |
FRβ | Targeted-folate-receptor beta |
GM-CSF | Granulocyte-macrophage colony stimulating factor |
HGF | Hepatocyte growth factor |
HIF-1 | Hypoxia-induced factor-1 |
IL | Interleukin |
IFN | Interferon |
iNOS | Inducible nitric oxide synthase |
MCTS | Multicellular tumor spheroids |
MDR | Multidrug resistance |
MDSCs | Myeloid-derived suppressive cells |
MMPs | Matrix metalloproteinases |
MT | Malignant transition |
NSCLC | Non-small cell lung cancer |
NK | Natural killer |
NKT | Natural killer T |
PD-1 | Programmed death 1 receptor |
PDMS | Polymethylsiloxane |
PlGF | Placental growth factor |
PDGF | Platelet-derived growth factor |
PHD-2 | Prolyl-hydroxylase enzyme-2 |
TAM | Tumor-associated macrophage |
TCDEs | Tumor cells derived exosomes |
TME | Tumor microenvironment |
TGF | Transforming growth factor |
TNF | Tumor necrosis factor |
Treg | Regulatory T cells |
VEGF | Vascular endothelial growth factor |
References
- Liu, J.; Dang, H.; Wang, X.W. The significance of intertumor and intratumor heterogeneity in liver cancer. Exp. Mol. Med. 2018, 50, e416. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Grzywa, T.M.; Paskal, W.; Wlodarski, P.K. Intratumor and intertumor heterogeneity in melanoma. Transl. Oncol. 2017, 10, 956–975. [Google Scholar] [CrossRef] [PubMed]
- Mroz, E.A.; Rocco, J.W. Intra-tumor heterogeneity in head and neck cancer and its clinical implications. World J. Otorhinolaryngol. Head Neck Surg. 2016, 2, 60–67. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stanta, G.; Bonin, S. Overview on clinical relevance of intra-tumor heterogeneity. Front. Med. 2018, 5, 85. [Google Scholar] [CrossRef] [PubMed]
- Wang, M.; Zhao, J.; Zhang, L.; Wei, F.; Lian, Y.; Wu, Y.; Gong, Z.; Zhang, S.; Zhou, J.; Cao, K.; et al. Role of tumor microenvironment in tumorigenesis. J. Cancer 2017, 8, 761–773. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, F.; Zhuang, X.; Lin, L.; Yu, P.; Wang, Y.; Shi, Y.; Hu, G.; Sun, Y. New horizons in tumor microenvironment biology: Challenges and opportunities. BMC Med. 2015, 13, 45. [Google Scholar] [CrossRef] [PubMed]
- Hanahan, D.; Coussens, L.M. Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell 2012, 21, 309–322. [Google Scholar] [CrossRef] [PubMed]
- Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed]
- Tahmasebi Birgani, M.; Carloni, V. Tumor microenvironment, a paradigm in hepatocellular carcinoma progression and therapy. Int. J. Mol. Sci. 2017, 18, 405. [Google Scholar] [CrossRef]
- Catalano, V.; Turdo, A.; Di Franco, S.; Dieli, F.; Todaro, M.; Stassi, G. Tumor and its microenvironment: A synergistic interplay. Semin. Cancer Biol. 2013, 23, 522–532. [Google Scholar] [CrossRef] [Green Version]
- Sormendi, S.; Wielockx, B. Hypoxia pathway proteins as central mediators of metabolism in the tumor cells and their microenvironment. Front. Immunol. 2018, 9, 40. [Google Scholar] [CrossRef] [PubMed]
- Netea-Maier, R.T.; Smit, J.W.A.; Netea, M.G. Metabolic changes in tumor cells and tumor-associated macrophages: A mutual relationship. Cancer Lett. 2018, 413, 102–109. [Google Scholar] [CrossRef] [PubMed]
- Abadjian, M.Z.; Edwards, W.B.; Anderson, C.J. Imaging the tumor microenvironment. Adv. Exp. Med. Biol. 2017, 1036, 229–257. [Google Scholar]
- Willumsen, N.; Thomsen, L.B.; Bager, C.L.; Jensen, C.; Karsdal, M.A. Quantification of altered tissue turnover in a liquid biopsy: A proposed precision medicine tool to assess chronic inflammation and desmoplasia associated with a pro-cancerous niche and response to immuno-therapeutic anti-tumor modalities. Cancer Immunol. Immunother. 2018, 67, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Wu, X.; Giobbie-Hurder, A.; Liao, X.; Connelly, C.; Connolly, E.M.; Li, J.; Manos, M.P.; Lawrence, D.; McDermott, D.; Severgnini, M.; et al. Angiopoietin-2 as a biomarker and target for immune checkpoint therapy. Cancer Immunol. Res. 2017, 5, 17–28. [Google Scholar] [CrossRef] [PubMed]
- Bjornmalm, M.; Thurecht, K.J.; Michael, M.; Scott, A.M.; Caruso, F. Bridging bio-nano science and cancer nanomedicine. ACS Nano 2017, 11, 9594–9613. [Google Scholar] [CrossRef] [PubMed]
- Tsai, M.J.; Chang, W.A.; Huang, M.S.; Kuo, P.L. Tumor microenvironment: A new treatment target for cancer. ISRN Biochem. 2014, 2014, 351959. [Google Scholar] [CrossRef]
- Vaupel, P.; Mayer, A. Hypoxia in tumors: Pathogenesis-related classification, characterization of hypoxia subtypes, and associated biological and clinical implications. Adv. Exp. Med. Biol. 2014, 812, 19–24. [Google Scholar]
- Masoud, G.N.; Li, W. HIF-1alpha pathway: Role, regulation and intervention for cancer therapy. Acta Pharm Sin B 2015, 5, 378–389. [Google Scholar] [CrossRef]
- Kim, S.Y. Cancer energy metabolism: Shutting power off cancer factory. Biomol. Ther. (Seoul) 2018, 26, 39–44. [Google Scholar] [CrossRef]
- Kato, Y.; Maeda, T.; Suzuki, A.; Baba, Y. Cancer metabolism: New insights into classic characteristics. Jpn. Dent. Sci. Rev. 2018, 54, 8–21. [Google Scholar] [CrossRef] [PubMed]
- Yuan, Y.; Jiang, Y.C.; Sun, C.K.; Chen, Q.M. Role of the tumor microenvironment in tumor progression and the clinical applications (review). Oncol. Rep. 2016, 35, 2499–2515. [Google Scholar] [CrossRef] [PubMed]
- Hui, L.; Chen, Y. Tumor microenvironment: Sanctuary of the devil. Cancer Lett. 2015, 368, 7–13. [Google Scholar] [CrossRef] [PubMed]
- Pickup, M.W.; Mouw, J.K.; Weaver, V.M. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 2014, 15, 1243–1253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Otranto, M.; Sarrazy, V.; Bonte, F.; Hinz, B.; Gabbiani, G.; Desmouliere, A. The role of the myofibroblast in tumor stroma remodeling. Cell Adhes. Migr. 2012, 6, 203–219. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Turunen, S.P.; Tatti-Bugaeva, O.; Lehti, K. Membrane-type matrix metalloproteases as diverse effectors of cancer progression. Biochim. Biophys. Acta 2017, 1864, 1974–1988. [Google Scholar] [CrossRef] [PubMed]
- Busby, J.; McMenamin, Ú.; Spence, A.; Johnston, B.T.; Hughes, C.; Cardwell, C.R. Angiotensin receptor blocker use and gastro-oesophageal cancer survival: A population-based cohort study. Aliment. Pharmacol. Ther. 2018, 47, 279–288. [Google Scholar] [CrossRef]
- Coulson, R.; Liew, S.H.; Connelly, A.A.; Yee, N.S.; Deb, S.; Kumar, B.; Vargas, A.C.; O’Toole, S.A.; Parslow, A.C.; Poh, A.; et al. The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma. Oncotarget 2017, 8, 18640–18656. [Google Scholar] [CrossRef]
- Diop-Frimpong, B.; Chauhan, V.P.; Krane, S.; Boucher, Y.; Jain, R.K. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc. Natl. Acad. Sci. USA 2011, 108, 2909–2914. [Google Scholar] [CrossRef] [Green Version]
- Cassinelli, G.; Lanzi, C.; Tortoreto, M.; Cominetti, D.; Petrangolini, G.; Favini, E.; Zaffaroni, N.; Pisano, C.; Penco, S.; Vlodavsky, I.; et al. Antitumor efficacy of the heparanase inhibitor SST0001 alone and in combination with antiangiogenic agents in the treatment of human pediatric sarcoma models. Biochem. Pharmacol. 2013, 85, 1424–1432. [Google Scholar] [CrossRef]
- Ritchie, J.P.; Ramani, V.C.; Ren, Y.; Naggi, A.; Torri, G.; Casu, B.; Penco, S.; Pisano, C.; Carminati, P.; Tortoreto, M.; et al. SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. Clin. Cancer Res. 2011, 17, 1382–1393. [Google Scholar] [CrossRef] [PubMed]
- Feng, S.; Agoulnik, I.U.; Bogatcheva, N.V.; Kamat, A.A.; Kwabi-Addo, B.; Li, R.; Ayala, G.; Ittmann, M.M.; Agoulnik, A.I. Relaxin promotes prostate cancer progression. Clin. Cancer Res. 2007, 13, 1695–1702. [Google Scholar] [CrossRef] [PubMed]
- Pujada, A.; Walter, L.; Patel, A.; Bui, T.A.; Zhang, Z.; Zhang, Y.; Denning, T.L.; Garg, P. Matrix metalloproteinase MMP9 maintains epithelial barrier function and preserves mucosal lining in colitis associated cancer. Oncotarget 2017, 8, 94650–94665. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Biondi, M.L.; Turri, O.; Leviti, S.; Seminati, R.; Cecchini, F.; Bernini, M.; Ghilardi, G.; Guagnellini, E. MMP1 and MMP3 polymorphisms in promoter regions and cancer. Clin. Chem. 2000, 46, 2023–2024. [Google Scholar] [PubMed]
- Zhou, Z.; Ma, X.; Wang, F.; Sun, L.; Zhang, G. A matrix metalloproteinase-1 polymorphism, MMP1–1607 (1G>2G), is associated with increased cancer risk: A meta-analysis including 21,327 patients. Dis. Markers 2018, 2018, 7565834. [Google Scholar] [CrossRef] [PubMed]
- Fakhoury, H.; Noureddine, S.; Chmaisse, H.N.; Tamim, H.; Makki, R.F. MMP1-1607(1G>2G) polymorphism and the risk of lung cancer in Lebanon. Ann. Thorac. Med. 2012, 7, 130–132. [Google Scholar] [CrossRef] [PubMed]
- Han, G.; Wei, Z.; Lu, Z.; Cui, H.; Bai, X.; Ge, H.; Zhang, W. Association between matrix metalloproteinase 1 -1607 1G>2G polymorphism and cancer risk: A meta-analysis including 19706 subjects. Int. J. Clin. Exp. Med. 2014, 7, 2992–2999. [Google Scholar] [PubMed]
- Chu, Q.S.; Forouzesh, B.; Syed, S.; Mita, M.; Schwartz, G.; Cooper, J.; Curtright, J.; Rowinsky, E.K. A phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas. Investig. New Drugs 2007, 25, 359–367. [Google Scholar] [CrossRef] [PubMed]
- Gu, Y.; Lee, H.M.; Golub, L.M.; Sorsa, T.; Konttinen, Y.T.; Simon, S.R. Inhibition of breast cancer cell extracellular matrix degradative activity by chemically modified tetracyclines. Ann Med 2005, 37, 450–460. [Google Scholar] [CrossRef]
- Fingleton, B. CMT-3. CollaGenex. Curr. Opin. Investig. Drugs 2003, 4, 1460–1467. [Google Scholar]
- Scannevin, R.H.; Alexander, R.; Haarlander, T.M.; Burke, S.L.; Singer, M.; Huo, C.; Zhang, Y.M.; Maguire, D.; Spurlino, J.; Deckman, I.; et al. Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation. J. Biol. Chem. 2017, 292, 17963–17974. [Google Scholar] [CrossRef] [PubMed]
- Ling, B.; Watt, K.; Banerjee, S.; Newsted, D.; Truesdell, P.; Adams, J.; Sidhu, S.S.; Craig, A.W.B. A novel immunotherapy targeting MMP-14 limits hypoxia, immune suppression and metastasis in triple-negative breast cancer models. Oncotarget 2017, 8, 58372–58385. [Google Scholar] [CrossRef] [PubMed]
- Vaupel, P.; Mayer, A. Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev. 2007, 26, 225–239. [Google Scholar] [CrossRef] [PubMed]
- Ziello, J.E.; Jovin, I.S.; Huang, Y. Hypoxia-inducible factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J. Biol. Med. 2007, 80, 51–60. [Google Scholar] [PubMed]
- Paolicchi, E.; Gemignani, F.; Krstic-Demonacos, M.; Dedhar, S.; Mutti, L.; Landi, S. Targeting hypoxic response for cancer therapy. Oncotarget 2016, 7, 13464–13478. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yu, T.; Tang, B.; Sun, X. Development of inhibitors targeting Hypoxia-Inducible Factor 1 and 2 for cancer therapy. Yonsei Med. J. 2017, 58, 489–496. [Google Scholar] [CrossRef]
- Duffy, A.G.; Melillo, G.; Turkbey, B.; Allen, D.; Choyke, P.L.; Chen, C.; Raffeld, M.; Doroshow, J.H.; Murgo, A.; Kummar, S. A pilot trial of oral topotecan (TPT) in patients with refractory advanced solid neoplasms expressing HIF-1α. J. Clin. Oncol. 2010, 28, e13518. [Google Scholar] [CrossRef]
- Iessi, E.; Logozzi, M.; Mizzoni, D.; Di Raimo, R.; Supuran, C.T.; Fais, S. Rethinking the combination of proton exchanger inhibitors in cancer therapy. Metabolites 2017, 8, 2. [Google Scholar] [CrossRef] [PubMed]
- Ikemura, K.; Hiramatsu, S.; Okuda, M. Drug Repositioning of Proton Pump Inhibitors for Enhanced Efficacy and Safety of Cancer Chemotherapy. Front. Pharm. 2017, 8, 911. [Google Scholar] [CrossRef]
- Kolosenko, I.; Avnet, S.; Baldini, N.; Viklund, J.; De Milito, A. Therapeutic implications of tumor interstitial acidification. Semin. Cancer Biol. 2017, 43, 119–133. [Google Scholar] [CrossRef]
- Izumi, H.; Torigoe, T.; Ishiguchi, H.; Uramoto, H.; Yoshida, Y.; Tanabe, M.; Ise, T.; Murakami, T.; Yoshida, T.; Nomoto, M.; et al. Cellular pH regulators: Potentially promising molecular targets for cancer chemotherapy. Cancer Treat. Rev. 2003, 29, 541–549. [Google Scholar] [CrossRef]
- Supuran, C.T. Advances in structure-based drug discovery of carbonic anhydrase inhibitors. Expert Opin. Drug Discov. 2017, 12, 61–88. [Google Scholar] [CrossRef]
- Supuran, C.T. Carbonic anhydrase inhibition and the management of hypoxic tumors. Metabolites 2017, 7, 48. [Google Scholar] [CrossRef]
- Singh, S.; Lomelino, C.L.; Mboge, M.Y.; Frost, S.C.; McKenna, R. Cancer drug development of carbonic anhydrase inhibitors beyond the active site. Molecules 2018, 23, 1045. [Google Scholar] [CrossRef]
- Nocentini, A.; Supuran, C.T. Carbonic anhydrase inhibitors as antitumor/antimetastatic agents: A patent review (2008–2018). Expert Opin. Ther. Pat. 2018, 28, 729–740. [Google Scholar] [CrossRef]
- Supuran, C.T. Carbonic anhydrase inhibitors as emerging agents for the treatment and imaging of hypoxic tumors. Expert Opin. Investig. Drugs 2018, 27, 963–970. [Google Scholar] [CrossRef]
- De Palma, M.; Biziato, D.; Petrova, T.V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 2017, 17, 457–474. [Google Scholar] [CrossRef]
- Klein, D. The tumor vascular endothelium as decision maker in cancer therapy. Front. Oncol. 2018, 8, 367. [Google Scholar] [CrossRef]
- Harrell, C.R.; Markovic, B.S.; Fellabaum, C.; Arsenijevic, A.; Djonov, V.; Volarevic, V. Molecular mechanisms underlying therapeutic potential of pericytes. J. Biomed. Sci. 2018, 25, 21. [Google Scholar] [CrossRef] [Green Version]
- Viallard, C.; Larrivée, B. Tumor angiogenesis and vascular normalization: Alternative therapeutic targets. Angiogenesis 2017, 20, 409–426. [Google Scholar] [CrossRef]
- Sounni, N.E.; Noel, A. Targeting the tumor microenvironment for cancer therapy. Clin. Chem. 2013, 59, 85–93. [Google Scholar] [CrossRef]
- Fukumura, D.; Jain, R.K. Tumor microenvironment abnormalities: Causes, consequences, and strategies to normalize. J. Cell. Biochem. 2007, 101, 937–949. [Google Scholar] [CrossRef]
- Lamberts, L.E.; Koch, M.; de Jong, J.S.; Adams, A.L.L.; Glatz, J.; Kranendonk, M.E.G.; Terwisscha van Scheltinga, A.G.T.; Jansen, L.; de Vries, J.; Lub-de Hooge, M.N.; et al. Tumor-specific uptake of fluorescent bevacizumab-irdye800cw microdosing in patients with primary breast cancer: A phase I feasibility study. Clin. Cancer Res. 2017, 23, 2730–2741. [Google Scholar] [CrossRef]
- Harlaar, N.J.; Koller, M.; de Jongh, S.J.; van Leeuwen, B.L.; Hemmer, P.H.; Kruijff, S.; van Ginkel, R.J.; Been, L.B.; de Jong, J.S.; Kats-Ugurlu, G.; et al. Molecular fluorescence-guided surgery of peritoneal carcinomatosis of colorectal origin: A single-centre feasibility study. Lancet Gastroenterol. Hepatol. 2016, 1, 283–290. [Google Scholar] [CrossRef]
- Jain, R.K. Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 2005, 307, 58–62. [Google Scholar] [CrossRef]
- Hamberg, P.; Verweij, J.; Sleijfer, S. (Pre-)clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor. Oncologist 2010, 15, 539–547. [Google Scholar] [CrossRef]
- Nakano, K.; Funauchi, Y.; Hayakawa, K.; Tanizawa, T.; Ae, K.; Matsumoto, S.; Takahashi, S. Relative dose intensity of induction-phase pazopanib treatment of soft tissue sarcoma: Its relationship with prognoses of pazopanib responders. J. Clin. Med. 2019, 8, 60. [Google Scholar] [CrossRef]
- Noda, S.; Yoshida, T.; Hira, D.; Murai, R.; Tomita, K.; Tsuru, T.; Kageyama, S.; Kawauchi, A.; Ikeda, Y.; Morita, S.Y.; et al. Exploratory investigation of target pazopanib concentration range for patients with renal cell carcinoma. Clin. Genitourin. Cancer 2018. [Google Scholar] [CrossRef]
- Wang, S.; Lu, J.; You, Q.; Huang, H.; Chen, Y.; Liu, K. The mTOR/AP-1/VEGF signaling pathway regulates vascular endothelial cell growth. Oncotarget 2016, 7, 53269–53276. [Google Scholar] [CrossRef] [Green Version]
- Chen, D.S.; Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 2017, 541, 321–330. [Google Scholar] [CrossRef]
- Clark, D.P. Biomarkers for immune checkpoint inhibitors: The importance of tumor topography and the challenges to cytopathology. Cancer Cytopathol. 2018, 126, 11–19. [Google Scholar] [CrossRef]
- Joyce, J.A. Therapeutic targeting of the tumor microenvironment. Cancer Cell 2005, 7, 513–520. [Google Scholar] [CrossRef] [Green Version]
- Shi, X.; Shiao, S.L. The role of macrophage phenotype in regulating the response to radiation therapy. Transl. Res. 2018, 191, 64–80. [Google Scholar] [CrossRef]
- Santoni, M.; Romagnoli, E.; Saladino, T.; Foghini, L.; Guarino, S.; Capponi, M.; Giannini, M.; Cognigni, P.D.; Ferrara, G.; Battelli, N. Triple negative breast cancer: Key role of tumor-associated macrophages in regulating the activity of anti-PD-1/PD-l1 agents. Biochim. Biophys. Acta 2018, 1869, 78–84. [Google Scholar] [CrossRef]
- Moraes, L.A.; Kar, S.; Foo, S.L.; Gu, T.; Toh, Y.Q.; Ampomah, P.B.; Sachaphibulkij, K.; Yap, G.; Zharkova, O.; Lukman, H.M.; et al. Annexin-A1 enhances breast cancer growth and migration by promoting alternative macrophage polarization in the tumour microenvironment. Sci. Rep. 2017, 7, 17925. [Google Scholar] [CrossRef] [Green Version]
- Seton-Rogers, S. Tumour immunology: Dendritic cell switch. Nat. Rev. Cancer 2012, 12, 230. [Google Scholar] [CrossRef]
- Seelige, R.; Searles, S.; Bui, J.D. Mechanisms regulating immune surveillance of cellular stress in cancer. Cell. Mol. Life Sci. 2018, 75, 225–240. [Google Scholar] [CrossRef]
- Chen, J.; Yao, Y.; Gong, C.; Yu, F.; Su, S.; Chen, J.; Liu, B.; Deng, H.; Wang, F.; Lin, L.; et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell 2011, 19, 541–555. [Google Scholar] [CrossRef]
- Barnes, T.A.; Amir, E. Hype or hope: The prognostic value of infiltrating immune cells in cancer. Br. J. Cancer 2017, 117, 451–460. [Google Scholar] [CrossRef]
- Schupp, J.; Krebs, F.K.; Zimmer, N.; Trzeciak, E.; Schuppan, D.; Tuettenberg, A. Targeting myeloid cells in the tumor sustaining microenvironment. Cell. Immunol. 2017. ahead of print. [Google Scholar] [CrossRef]
- Helfen, A.; Roth, J.; Ng, T.; Eisenblaetter, M. In vivo imaging of pro- and antitumoral cellular components of the tumor microenvironment. J. Nucl. Med. 2018, 59, 183–188. [Google Scholar] [CrossRef]
- Sica, A.; Porta, C.; Amadori, A.; Pasto, A. Tumor-associated myeloid cells as guiding forces of cancer cell stemness. Cancer Immunol. Immunother. 2017, 66, 1025–1036. [Google Scholar] [CrossRef]
- Szebeni, G.J.; Vizler, C.; Nagy, L.I.; Kitajka, K.; Puskas, L.G. Pro-tumoral inflammatory myeloid cells as emerging therapeutic targets. Int. J. Mol. Sci. 2016, 17, 1958. [Google Scholar] [CrossRef]
- Mantovani, A.; Marchesi, F.; Malesci, A.; Laghi, L.; Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 2017, 14, 399–416. [Google Scholar] [CrossRef]
- Noy, R.; Pollard, J.W. Tumor-associated macrophages: From mechanisms to therapy. Immunity 2014, 41, 49–61. [Google Scholar] [CrossRef]
- Holmgaard, R.B.; Zamarin, D.; Lesokhin, A.; Merghoub, T.; Wolchok, J.D. Targeting myeloid-derived suppressor cells with colony stimulating factor-1 receptor blockade can reverse immune resistance to immunotherapy in indoleamine 2,3-dioxygenase-expressing tumors. EBioMedicine 2016, 6, 50–58. [Google Scholar] [CrossRef] [Green Version]
- Patel, S.; Player, M.R. Colony-stimulating factor-1 receptor inhibitors for the treatment of cancer and inflammatory disease. Curr. Top. Med. Chem. 2009, 9, 599–610. [Google Scholar] [CrossRef]
- Komohara, Y.; Fujiwara, Y.; Ohnishi, K.; Takeya, M. Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. Adv. Drug Deliv. Rev. 2016, 99, 180–185. [Google Scholar] [CrossRef]
- Larkin, J.; Ascierto, P.A.; Dréno, B.; Atkinson, V.; Liszkay, G.; Maio, M.; Mandalà, M.; Demidov, L.; Stroyakovskiy, D.; Thomas, L.; et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl. J. Med. 2014, 371, 1867–1876. [Google Scholar] [CrossRef]
- Schilling, B.; Sucker, A.; Griewank, K.; Zhao, F.; Weide, B.; Gorgens, A.; Giebel, B.; Schadendorf, D.; Paschen, A. Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. Int. J. Cancer 2013, 133, 1653–1663. [Google Scholar] [CrossRef] [Green Version]
- Na, Y.R.; Je, S.; Seok, S.H. Metabolic features of macrophages in inflammatory diseases and cancer. Cancer Lett. 2018, 413, 46–58. [Google Scholar] [CrossRef]
- Dvorak, H.F. Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 1986, 315, 1650–1659. [Google Scholar]
- DeNardo, D.G.; Andreu, P.; Coussens, L.M. Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev. 2010, 29, 309–316. [Google Scholar] [CrossRef] [Green Version]
- Jiang, H.; Hegde, S.; DeNardo, D.G. Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy. Cancer Immunol. Immunother. 2017, 66, 1037–1048. [Google Scholar] [CrossRef]
- Grivennikov, S.I.; Greten, F.R.; Karin, M. Immunity, inflammation, and cancer. Cell 2010, 140, 883–899. [Google Scholar] [CrossRef]
- Qian, B.Z.; Pollard, J.W. Macrophage diversity enhances tumor progression and metastasis. Cell 2010, 141, 39–51. [Google Scholar] [CrossRef]
- Tashireva, L.A.; Perelmuter, V.M.; Manskikh, V.N.; Denisov, E.V.; Savelieva, O.E.; Kaygorodova, E.V.; Zavyalova, M.V. Types of immune-inflammatory responses as a reflection of cell-cell interactions under conditions of tissue regeneration and tumor growth. Biochemistry (Moscow) 2017, 82, 542–555. [Google Scholar] [CrossRef]
- Mantovani, A.; Barajon, I.; Garlanda, C. IL-1 and IL-1 regulatory pathways in cancer progression and therapy. Immunol. Rev. 2018, 281, 57–61. [Google Scholar] [CrossRef]
- Holen, I.; Lefley, D.V.; Francis, S.E.; Rennicks, S.; Bradbury, S.; Coleman, R.E.; Ottewell, P. IL-1 drives breast cancer growth and bone metastasis in vivo. Oncotarget 2016, 7, 75571–75584. [Google Scholar] [CrossRef] [Green Version]
- Tulotta, C.; Ottewell, P. The role of IL-1B in breast cancer bone metastasis. Endocr. Relat. Cancer 2018, 25, R421–R434. [Google Scholar] [CrossRef] [Green Version]
- Ridker, P.M.; MacFadyen, J.G.; Thuren, T.; Everett, B.M.; Libby, P.; Glynn, R.J. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: Exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 2017, 390, 1833–1842. [Google Scholar] [CrossRef]
- Meirovitz, A.; Goldberg, R.; Binder, A.; Rubinstein, A.M.; Hermano, E.; Elkin, M. Heparanase in inflammation and inflammation-associated cancer. FEBS J. 2013, 280, 2307–2319. [Google Scholar] [CrossRef] [PubMed]
- Wang, J.; He, X.D.; Yao, N.; Liang, W.J.; Zhang, Y.C. A meta-analysis of adjuvant therapy after potentially curative treatment for hepatocellular carcinoma. Can. J. Gastroenterol. 2013, 27, 351–363. [Google Scholar] [CrossRef] [PubMed]
- Restifo, N.P.; Dudley, M.E.; Rosenberg, S.A. Adoptive immunotherapy for cancer: Harnessing the T cell response. Nat. Rev. Immunol. 2012, 12, 269–281. [Google Scholar] [CrossRef] [PubMed]
- Setrerrahmane, S.; Xu, H. Tumor-related interleukins: Old validated targets for new anti-cancer drug development. Mol. Cancer 2017, 16, 153. [Google Scholar] [CrossRef] [PubMed]
- Vivier, E.; Tomasello, E.; Baratin, M.; Walzer, T.; Ugolini, S. Functions of Natural Killer cells. Nat. Immunol. 2008, 9, 503–510. [Google Scholar] [CrossRef] [PubMed]
- Waldmann, T.A. Cytokines in cancer immunotherapy. Cold Spring Harb. Perspect. Biol. 2018, 10, a028472. [Google Scholar] [CrossRef]
- De Remigis, A.; de Gruijl, T.D.; Uram, J.N.; Tzou, S.C.; Iwama, S.; Talor, M.V.; Armstrong, T.D.; Santegoets, S.J.; Slovin, S.F.; Zheng, L.; et al. Development of thyroglobulin antibodies after GVAX immunotherapy is associated with prolonged survival. Int. J. Cancer 2015, 136, 127–137. [Google Scholar] [CrossRef]
- Lipson, E.J.; Sharfman, W.H.; Chen, S.; McMiller, T.L.; Pritchard, T.S.; Salas, J.T.; Sartorius-Mergenthaler, S.; Freed, I.; Ravi, S.; Wang, H.; et al. Safety and immunologic correlates of Melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting. J. Transl. Med. 2015, 13, 214. [Google Scholar] [CrossRef]
- Santegoets, S.J.; Stam, A.G.; Lougheed, S.M.; Gall, H.; Jooss, K.; Sacks, N.; Hege, K.; Lowy, I.; Scheper, R.J.; Gerritsen, W.R.; et al. Myeloid derived suppressor and dendritic cell subsets are related to clinical outcome in prostate cancer patients treated with prostate GVAX and ipilimumab. J. Immunother. Cancer 2014, 2, 31. [Google Scholar] [CrossRef] [Green Version]
- Nemunaitis, J. GVAX (GMCSF gene modified tumor vaccine) in advanced stage non small cell lung cancer. J. Control. Release 2003, 91, 225–231. [Google Scholar] [CrossRef]
- Darvin, P.; Toor, S.M.; Nair, V.S.; Elkord, E. Immune checkpoint inhibitors: Recent progress and potential biomarkers. Exp. Mol. Med. 2018, 50, 165. [Google Scholar] [CrossRef] [PubMed]
- Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12, 252–264. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhao, B.; Zhao, H.; Zhao, J. Serious adverse events and fatal adverse events associated with nivolumab treatment in cancer patients: Nivolumab-related serious/fatal adverse events. J. Immunother. Cancer 2018, 6, 101. [Google Scholar] [CrossRef] [PubMed]
- Chen, T.; Li, Q.; Liu, Z.; Chen, Y.; Feng, F.; Sun, H. Peptide-based and small synthetic molecule inhibitors on PD-1/PD-L1 pathway: A new choice for immunotherapy? Eur. J. Med. Chem. 2019, 161, 378–398. [Google Scholar] [CrossRef] [PubMed]
- Boohaker, R.J.; Sambandam, V.; Segura, I.; Miller, J.; Suto, M.; Xu, B. Rational design and development of a peptide inhibitor for the PD-1/PD-L1 interaction. Cancer Lett. 2018, 434, 11–21. [Google Scholar] [CrossRef] [PubMed]
- Torphy, R.J.; Schulick, R.D.; Zhu, Y. Newly emerging immune checkpoints: Promises for future cancer therapy. Int. J. Mol. Sci. 2017, 18, 2642. [Google Scholar] [CrossRef]
- Rivera-Cruz, C.M.; Shearer, J.J.; Figueiredo Neto, M.; Figueiredo, M.L. The immunomodulatory effects of mesenchymal stem cell polarization within the tumor microenvironment niche. Stem Cells Int. 2017, 2017, 4015039. [Google Scholar] [CrossRef]
- Trivanovic, D.; Krstic, J.; Djordjevic, I.O.; Mojsilovic, S.; Santibanez, J.F.; Bugarski, D.; Jaukovic, A. The roles of mesenchymal stromal/stem cells in tumor microenvironment associated with inflammation. Mediat. Inflamm. 2016, 2016, 7314016. [Google Scholar] [CrossRef]
- Lamprecht, S.; Sigal-Batikoff, I.; Shany, S.; Abu-Freha, N.; Ling, E.; Delinasios, G.J.; Moyal-Atias, K.; Delinasios, J.G.; Fich, A. Teaming up for trouble: Cancer cells, transforming growth factor-beta1 signaling and the epigenetic corruption of stromal naive fibroblasts. Cancers 2018, 10, 61. [Google Scholar] [CrossRef]
- Ray, A.; Cleary, M.P. The potential role of leptin in tumor invasion and metastasis. Cytokine Growth Factor Rev. 2017, 38, 80–97. [Google Scholar] [CrossRef] [PubMed]
- Coletta, R.D.; Salo, T. Myofibroblasts in oral potentially malignant disorders: Is it related to malignant transformation? Oral Dis. 2018, 24, 84–88. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yang, Z.; Yang, X.; Xu, S.; Jin, P.; Li, X.; Wei, X.; Liu, D.; Huang, K.; Long, S.; Wang, Y.; et al. Reprogramming of stromal fibroblasts by SNAI2 contributes to tumor desmoplasia and ovarian cancer progression. Mol. Cancer 2017, 16, 163. [Google Scholar] [CrossRef] [PubMed]
- Ishii, N.; Araki, K.; Yokobori, T.; Hagiwara, K.; Gantumur, D.; Yamanaka, T.; Handa, T.; Tsukagoshi, M.; Igarashi, T.; Watanabe, A.; et al. Conophylline suppresses pancreatic cancer desmoplasia and cancer-promoting cytokines produced by cancer-associated fibroblasts. Cancer Sci. 2018. ahead of print. [Google Scholar] [CrossRef] [PubMed]
- Keerthikumar, S.; Chisanga, D.; Ariyaratne, D.; Al Saffar, H.; Anand, S.; Zhao, K.; Samuel, M.; Pathan, M.; Jois, M.; Chilamkurti, N.; et al. Exocarta: A web-based compendium of exosomal cargo. J. Mol. Biol. 2016, 428, 688–692. [Google Scholar] [CrossRef] [PubMed]
- Park, J.E.; Tan, H.S.; Datta, A.; Lai, R.C.; Zhang, H.; Meng, W.; Lim, S.K.; Sze, S.K. Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol. Cell. Proteom. 2010, 9, 1085–1099. [Google Scholar] [CrossRef] [PubMed]
- Clayton, A.; Turkes, A.; Navabi, H.; Mason, M.D.; Tabi, Z. Induction of heat shock proteins in B-cell exosomes. J. Cell Sci. 2005, 118, 3631–3638. [Google Scholar] [CrossRef] [Green Version]
- Taraboletti, G.; D’Ascenzo, S.; Giusti, I.; Marchetti, D.; Borsotti, P.; Millimaggi, D.; Giavazzi, R.; Pavan, A.; Dolo, V. Bioavailability of VEGF in tumor-shed vesicles depends on vesicle burst induced by acidic pH. Neoplasia 2006, 8, 96–103. [Google Scholar] [CrossRef]
- Savina, A.; Furlan, M.; Vidal, M.; Colombo, M.I. Exosome release is regulated by a calcium-dependent mechanism in k562 cells. J. Biol. Chem. 2003, 278, 20083–20090. [Google Scholar] [CrossRef]
- Graner, M.W.; Cumming, R.I.; Bigner, D.D. The heat shock response and chaperones/heat shock proteins in brain tumors: Surface expression, release, and possible immune consequences. J. Neurosci. 2007, 27, 11214–11227. [Google Scholar] [CrossRef]
- Koumangoye, R.B.; Sakwe, A.M.; Goodwin, J.S.; Patel, T.; Ochieng, J. Detachment of breast tumor cells induces rapid secretion of exosomes which subsequently mediate cellular adhesion and spreading. PLoS ONE 2011, 6, e24234. [Google Scholar] [CrossRef] [PubMed]
- Lenassi, M.; Cagney, G.; Liao, M.; Vaupotic, T.; Bartholomeeusen, K.; Cheng, Y.; Krogan, N.J.; Plemenitas, A.; Peterlin, B.M. HIV NEF is secreted in exosomes and triggers apoptosis in bystander CD4+ T cells. Traffic 2010, 11, 110–122. [Google Scholar] [CrossRef] [PubMed]
- Roma-Rodrigues, C.; Pereira, F.; Alves de Matos, A.P.; Fernandes, M.; Baptista, P.V.; Fernandes, A.R. Smuggling gold nanoparticles across cell types—A new role for exosomes in gene silencing. Nanomedicine 2017, 13, 1389–1398. [Google Scholar] [CrossRef] [PubMed]
- Franzen, C.A.; Simms, P.E.; Van Huis, A.F.; Foreman, K.E.; Kuo, P.C.; Gupta, G.N. Characterization of uptake and internalization of exosomes by bladder cancer cells. Biomed. Res. Int. 2014, 2014, 619829. [Google Scholar] [CrossRef] [PubMed]
- Roma-Rodrigues, C.; Fernandes, A.R.; Baptista, P.V. Exosome in tumour microenvironment: Overview of the crosstalk between normal and cancer cells. Biomed. Res. Int. 2014, 2014, 179486. [Google Scholar] [CrossRef] [PubMed]
- Sauter, E.R. Exosomes in lymph and cancer. Transl. Cancer Res. 2017, 6, S1311–S1315. [Google Scholar] [CrossRef]
- Sauter, E.R. Exosomes in blood and cancer. Transl. Cancer Res. 2017, 6, S1316–S1320. [Google Scholar] [CrossRef]
- Steinbichler, T.B.; Dudas, J.; Riechelmann, H.; Skvortsova, I.I. The role of exosomes in cancer metastasis. Semin. Cancer Biol. 2017, 44, 170–181. [Google Scholar] [CrossRef]
- Ruivo, C.F.; Adem, B.; Silva, M.; Melo, S.A. The biology of cancer exosomes: Insights and new perspectives. Cancer Res. 2017, 77, 6480–6488. [Google Scholar] [CrossRef]
- Graner, M.W.; Schnell, S.; Olin, M.R. Tumor-derived exosomes, microRNAs, and cancer immune suppression. Semin. Immunopathol. 2018. ahead of print. [Google Scholar] [CrossRef]
- Lopez-Paniagua, M.; Nieto-Miguel, T.; de la Mata, A.; Dziasko, M.; Galindo, S.; Rey, E.; Herreras, J.M.; Corrales, R.M.; Daniels, J.T.; Calonge, M. Comparison of functional limbal epithelial stem cell isolation methods. Exp. Eye Res. 2016, 146, 83–94. [Google Scholar] [CrossRef]
- Muralidharan-Chari, V.; Clancy, J.W.; Sedgwick, A.; D’Souza-Schorey, C. Microvesicles: Mediators of extracellular communication during cancer progression. J. Cell Sci. 2010, 123, 1603–1611. [Google Scholar] [CrossRef] [PubMed]
- Zhou, Y.; Ren, H.; Dai, B.; Li, J.; Shang, L.; Huang, J.; Shi, X. Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts. J. Exp. Clin. Cancer Res. 2018, 37, 324. [Google Scholar] [CrossRef] [PubMed]
- Rai, A.; Greening, D.W.; Chen, M.; Xu, R.; Ji, H.; Simpson, R.J. Exosomes Derived from Human Primary and Metastatic Colorectal Cancer Cells Contribute to Functional Heterogeneity of Activated Fibroblasts by Reprogramming Their Proteome. Proteomics 2018, e1800148. [Google Scholar] [CrossRef] [PubMed]
- Capello, M.; Vykoukal, J.V.; Katayama, H.; Bantis, L.E.; Wang, H.; Kundnani, D.L.; Aguilar-Bonavides, C.; Aguilar, M.; Tripathi, S.C.; Dhillon, D.S.; et al. Exosomes harbor B cell targets in pancreatic adenocarcinoma and exert decoy function against complement-mediated cytotoxicity. Nat. Commun. 2019, 10, 254. [Google Scholar] [CrossRef] [PubMed]
- Conigliaro, A.; Cicchini, C. Exosome-Mediated Signaling in Epithelial to Mesenchymal Transition and Tumor Progression. J. Clin. Med. 2018, 8, 26. [Google Scholar] [CrossRef] [PubMed]
- Gao, D.; Jiang, L. Exosomes in cancer therapy: A novel experimental strategy. Am. J. Cancer Res. 2018, 8, 2165–2175. [Google Scholar] [PubMed]
- Yousafzai, N.A.; Wang, H.; Wang, Z.; Zhu, Y.; Zhu, L.; Jin, H.; Wang, X. Exosome mediated multidrug resistance in cancer. Am. J. Cancer Res. 2018, 8, 2210–2226. [Google Scholar] [PubMed]
- Roma-Rodrigues, C.; Raposo, L.R.; Cabral, R.; Paradinha, F.; Baptista, P.V.; Fernandes, A.R. Tumor microenvironment modulation via gold nanoparticles targeting malicious exosomes: Implications for cancer diagnostics and therapy. Int. J. Mol. Sci. 2017, 18, 162. [Google Scholar] [CrossRef]
- Ostrowski, M.; Carmo, N.B.; Krumeich, S.; Fanget, I.; Raposo, G.; Savina, A.; Moita, C.F.; Schauer, K.; Hume, A.N.; Freitas, R.P.; et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat. Cell Biol. 2010, 12, 19–30. [Google Scholar] [CrossRef]
- Bobrie, A.; Krumeich, S.; Reyal, F.; Recchi, C.; Moita, L.F.; Seabra, M.C.; Ostrowski, M.; Théry, C. RAB27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Res. 2012, 72, 4920–4930. [Google Scholar] [CrossRef] [PubMed]
- Lane, D. Designer combination therapy for cancer. Nat. Biotechnol. 2006, 24, 163–164. [Google Scholar] [CrossRef]
- Mendes, R.; Fernandes, A.R.; Baptista, P.V. Gold nanoparticle approach to the selective delivery of gene silencing in cancer-the case for combined delivery? Genes 2017, 8, 94. [Google Scholar] [CrossRef] [PubMed]
- Mokhtari, R.B.; Homayouni, T.S.; Baluch, N.; Morgatskaya, E.; Kumar, S.; Das, B.; Yeger, H. Combination therapy in combating cancer. Oncotarget 2015, 8, 38022–38043. [Google Scholar] [CrossRef] [PubMed]
- Frei, E., 3rd; Freireich, E.J. Progress and perpectives in the chemotherapy of acute leukemia. Adv. Chemother. 1965, 2, 269–298. [Google Scholar]
- Mangiameli, D.P.; Blansfield, J.A.; Kachala, S.; Lorang, D.; Schafer, P.H.; Muller, G.W.; Stirling, D.I.; Libutti, S.K. Combination therapy targeting the tumor microenvironment is effective in a model of human ocular melanoma. J. Transl. Med. 2007, 5, 38. [Google Scholar] [CrossRef] [Green Version]
- Kitano, H.; Kitadai, Y.; Teishima, J.; Yuge, R.; Shinmei, S.; Goto, K.; Inoue, S.; Hayashi, T.; Sentani, K.; Yasui, W.; et al. Combination therapy using molecular-targeted drugs modulates tumor microenvironment and impairs tumor growth in renal cell carcinoma. Cancer Med. 2017, 6, 2308–2320. [Google Scholar] [CrossRef] [Green Version]
- Allen, E.; Jabouille, A.; Rivera, L.B.; Lodewijckx, I.; Missiaen, R.; Steri, V.; Feyen, K.; Tawney, J.; Hanahan, D.; Michael, I.P.; et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl. Med. 2017, 9, eaak9679. [Google Scholar] [CrossRef]
- Aparicio, L.M.A.; Fernandez, I.P.; Cassinello, J. Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: Rethinking cancer immunotherapy. Clin. Transl. Oncol. 2017, 19, 1175–1182. [Google Scholar] [CrossRef]
- Duchnowska, R.; Loibl, S.; Jassem, J. Tyrosine kinase inhibitors for brain metastases in HER2-positive breast cancer. Cancer Treat. Rev. 2018, 67, 71–77. [Google Scholar] [CrossRef]
- Ntanasis-Stathopoulos, I.; Fotopoulos, G.; Tzanninis, I.G.; Kotteas, E.A. The emerging role of tyrosine kinase inhibitors in ovarian cancer treatment: A systematic review. Cancer Investig. 2016, 34, 313–339. [Google Scholar] [CrossRef] [PubMed]
- Matos, I.; Elez, E.; Capdevila, J.; Tabernero, J. Emerging tyrosine kinase inhibitors for the treatment of metastatic colorectal cancer. Expert Opin. Emerg. Drugs 2016, 21, 267–282. [Google Scholar] [CrossRef] [PubMed]
- Giordani, E.; Zoratto, F.; Strudel, M.; Papa, A.; Rossi, L.; Minozzi, M.; Caruso, D.; Zaccarelli, E.; Verrico, M.; Tomao, S. Old tyrosine kinase inhibitors and newcomers in gastrointestinal cancer treatment. Curr. Cancer Drug Targets 2016, 16, 175–185. [Google Scholar] [PubMed]
- De Falco, V.; Carlomagno, F.; Li, H.Y.; Santoro, M. The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer. Best Pract. Res Clin. Endocrinol. Metab. 2017, 31, 307–318. [Google Scholar] [CrossRef] [PubMed]
- Sgambato, A.; Casaluce, F.; Maione, P.; Gridelli, C. Targeted therapies in non-small cell lung cancer: A focus on ALK/ROS1 tyrosine kinase inhibitors. Expert Rev. Anticancer 2018, 18, 71–80. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Gu, J. Risk of gastrointestinal events with newly approved (after 2011) vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: A meta-analysis of randomized controlled trials. Eur. J. Clin. Pharm. 2017, 73, 1209–1217. [Google Scholar] [CrossRef] [PubMed]
- Herrmann, J. Tyrosine Kinase Inhibitors and Vascular Toxicity: Impetus for a Classification System? Curr. Oncol. Rep. 2016, 18, 33. [Google Scholar] [CrossRef] [PubMed]
- Danhier, F.; Feron, O.; Preat, V. To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J. Control. Release 2010, 148, 135–146. [Google Scholar] [CrossRef]
- Von Roemeling, C.; Jiang, W.; Chan, C.K.; Weissman, I.L.; Kim, B.Y.S. Breaking down the barriers to precision cancer nanomedicine. Trends Biotechnol. 2017, 35, 159–171. [Google Scholar] [CrossRef]
- Leong, D.T.; Ng, K.W. Probing the relevance of 3D cancer models in nanomedicine research. Adv. Drug Deliv. Rev. 2014, 79–80, 95–106. [Google Scholar] [CrossRef]
- Tong, R.; Langer, R. Nanomedicines targeting the tumor microenvironment. Cancer J. 2015, 21, 314–321. [Google Scholar] [CrossRef] [PubMed]
- Danhier, F. To exploit the tumor microenvironment: Since the epr effect fails in the clinic, what is the future of nanomedicine? J. Control. Release 2016, 244, 108–121. [Google Scholar] [CrossRef] [PubMed]
- Overchuk, M.; Zheng, G. Overcoming obstacles in the tumor microenvironment: Recent advancements in nanoparticle delivery for cancer theranostics. Biomaterials 2018, 156, 217–237. [Google Scholar] [CrossRef] [PubMed]
- Fernandes, A.R.; Jesus, J.; Martins, P.; Figueiredo, S.; Rosa, D.; Martins, L.M.; Corvo, M.L.; Carvalheiro, M.C.; Costa, P.M.; Baptista, P.V. Multifunctional gold-nanoparticles: A nanovectorization tool for the targeted delivery of novel chemotherapeutic agents. J. Control. Release 2017, 245, 52–61. [Google Scholar] [CrossRef] [PubMed]
- Chauhan, V.P.; Jain, R.K. Strategies for advancing cancer nanomedicine. Nat. Mater. 2013, 12, 958–962. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mardhian, D.F.; Storm, G.; Bansal, R.; Prakash, J. Nano-targeted relaxin impairs fibrosis and tumor growth in pancreatic cancer and improves the efficacy of gemcitabine in vivo. J. Control. Release 2018, 290, 1–10. [Google Scholar] [CrossRef] [PubMed]
- Roma-Rodrigues, C.; Heuer-Jungemann, A.; Fernandes, A.R.; Kanaras, A.G.; Baptista, P.V. Peptide-coated gold nanoparticles for modulation of angiogensis in vivo. Int. J. Nanomed. 2016, 11, 2633–2639. [Google Scholar]
- Wang, Y.; Cuzzucoli, F.; Escobar, A.; Lu, S.; Liang, L.; Wang, S.Q. Tumor-on-a-chip platforms for assessing nanoparticle-based cancer therapy. Nanotechnology 2018, 29, 332001. [Google Scholar] [CrossRef] [Green Version]
- Yao, Q.; Kou, L.; Zhu, L. MMP-responsive ‘smart’ drug delivery and tumor targeting. Trends Pharm. Sci. 2018, 39, 766–781. [Google Scholar] [CrossRef]
- Siegler, E.L.; Kim, Y.J.; Wang, P. Nanomedicine targeting the tumor microenvironment: Therapeutic strategies to inhibit angiogenesis, remodel matrix, and modulate immune responses. J. Cell. Immunother. 2016, 2, 69–78. [Google Scholar] [CrossRef] [Green Version]
- Adjei, I.M.; Blanka, S. Modulation of the tumor microenvironment for cancer treatment: A biomaterials approach. J. Funct. Biomater. 2015, 6, 81–103. [Google Scholar] [CrossRef] [PubMed]
- Unger, C.; Kramer, N.; Walzl, A.; Scherzer, M.; Hengstschlager, M.; Dolznig, H. Modeling human carcinomas: Physiologically relevant 3D models to improve anti-cancer drug development. Adv. Drug Deliv. Rev. 2014, 79–80, 50–67. [Google Scholar] [CrossRef] [PubMed]
- Wang, C.; Tang, Z.; Zhao, Y.; Yao, R.; Li, L.; Sun, W. Three-dimensional in vitro cancer models: A short review. Biofabrication 2014, 6, 022001. [Google Scholar] [CrossRef] [PubMed]
- Costa, E.C.; Moreira, A.F.; de Melo-Diogo, D.; Gaspar, V.M.; Carvalho, M.P.; Correia, I.J. 3D tumor spheroids: An overview on the tools and techniques used for their analysis. Biotechnol. Adv. 2016, 34, 1427–1441. [Google Scholar] [CrossRef]
- Villasante, A.; Vunjak-Novakovic, G. Tissue-engineered models of human tumors for cancer research. Expert Opin. Drug Discov. 2015, 10, 257–268. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Larson, B. 3D cell culture: A review of current techniques. BioTek 2015, 6, 1–10. [Google Scholar]
- Pampaloni, F.; Reynaud, E.G.; Stelzer, E.H. The third dimension bridges the gap between cell culture and live tissue. Nat. Rev. Mol. Cell. Biol. 2007, 8, 839–845. [Google Scholar] [CrossRef]
- Lovitt, C.J.; Shelper, T.B.; Avery, V.M. Advanced cell culture techniques for cancer drug discovery. Biology (Basel) 2014, 3, 345–367. [Google Scholar] [CrossRef] [PubMed]
- Nath, S.; Devi, G.R. Three-dimensional culture systems in cancer research: Focus on tumor spheroid model. Pharm. Ther. 2016, 163, 94–108. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Haycock, J.W. 3d cell culture: A review of current approaches and techniques. Methods Mol. Biol. 2011, 695, 1–15. [Google Scholar] [PubMed]
- Benien, P.; Swami, A. 3D tumor models: History, advances and future perspectives. Future Oncol. 2014, 10, 1311–1327. [Google Scholar] [CrossRef] [PubMed]
- Santo, V.E.; Rebelo, S.P.; Estrada, M.F.; Alves, P.M.; Boghaert, E.; Brito, C. Drug screening in 3D in vitro tumor models: Overcoming current pitfalls of efficacy read-outs. Biotechnol. J. 2017, 12. [Google Scholar] [CrossRef] [PubMed]
- Tsai, H.F.; Trubelja, A.; Shen, A.Q.; Bao, G. Tumour-on-a-chip: Microfluidic models of tumour morphology, growth and microenvironment. J. R. Soc. Interface 2017, 14. [Google Scholar] [CrossRef] [PubMed]
- Huh, D.; Hamilton, G.A.; Ingber, D.E. From 3D cell culture to organs-on-chips. Trends Cell Biol. 2011, 21, 745–754. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Carvalho, M.R.; Lima, D.; Reis, R.L.; Correlo, V.M.; Oliveira, J.M. Evaluating biomaterial- and microfluidic-based 3D tumor models. Trends Biotechnol. 2015, 33, 667–678. [Google Scholar] [CrossRef] [PubMed]
- Ahn, J.; Sei, Y.J.; Jeon, N.L.; Kim, Y. Tumor microenvironment on a chip: The progress and future perspective. Bioengineering (Basel) 2017, 4, 64. [Google Scholar] [CrossRef] [PubMed]
- Huang, Y.L.; Segall, J.E.; Wu, M. Microfluidic modeling of the biophysical microenvironment in tumor cell invasion. Lab Chip 2017, 17, 3221–3233. [Google Scholar] [CrossRef]
- Kashaninejad, N.; Nikmaneshi, M.; Moghadas, H.; Kiyoumarsi Oskouei, A.; Rismanian, M.; Barisam, M.; Saidi, M.; Firoozabadi, B. Organ-tumor-on-a-chip for chemosensitivity assay: A critical review. Micromachines 2016, 7, 130. [Google Scholar] [CrossRef]
- Sung, K.E.; Beebe, D.J. Microfluidic 3D models of cancer. Adv. Drug Deliv. Rev. 2014, 79–80, 68–78. [Google Scholar] [CrossRef]
- Han, B.; Qu, C.; Park, K.; Konieczny, S.F.; Korc, M. Recapitulation of complex transport and action of drugs at the tumor microenvironment using tumor-microenvironment-on-chip. Cancer Lett. 2016, 380, 319–329. [Google Scholar] [CrossRef] [Green Version]
- Yamada, K.M.; Cukierman, E. Modeling tissue morphogenesis and cancer in 3D. Cell 2007, 130, 601–610. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.S.; Zhang, Y.N.; Zhang, W. Cancer-on-a-chip systems at the frontier of nanomedicine. Drug Discov. Today 2017, 22, 1392–1399. [Google Scholar] [CrossRef] [PubMed]
- Hachey, S.J.; Hughes, C.C.W. Applications of tumor chip technology. Lab Chip 2018, 18, 2893–2912. [Google Scholar] [CrossRef] [PubMed]
- Kumar, V.; Varghese, S. Ex vivo Tumor-on-a-chip platforms to study intercellular interactions within tumor microenvironment. Adv. Healthc. Mater. 2018, e1801198. [Google Scholar] [CrossRef] [PubMed]
- Lu, S.; Cuzzucoli, F.; Jiang, J.; Liang, L.G.; Wang, Y.; Kong, M.; Zhao, X.; Cui, W.; Li, J.; Wang, S. Development of a biomimetic liver tumor-on-a-chip model based on decellularized liver matrix for toxicity testing. Lab Chip 2018, 18, 3379–3392. [Google Scholar] [CrossRef] [PubMed]
- Aleman, J.; Skardal, A. A multi-site metastasis-on-a-chip microphysiological system for assessing metastatic preference of cancer cells. Biotechnol. Bioeng. 2018. ahead of print. [Google Scholar] [CrossRef] [PubMed]
- Mazzocchi, A.R.; Rajan, S.A.P.; Votanopoulos, K.I.; Hall, A.R.; Skardal, A. In vitro patient-derived 3D mesothelioma tumor organoids facilitate patient-centric therapeutic screening. Sci. Rep. 2018, 8, 2886. [Google Scholar] [CrossRef]
- Shirure, V.S.; Bi, Y.; Curtis, M.B.; Lezia, A.; Goedegebuure, M.M.; Goedegebuure, S.P.; Aft, R.; Fields, R.C.; George, S.C. Tumor-on-a-chip platform to investigate progression and drug sensitivity in cell lines and patient-derived organoids. Lab Chip 2018, 18, 3687–3702. [Google Scholar] [CrossRef]
- Hayashi, Y.; Emoto, T.; Futaki, S.; Sekiguchi, K. Establishment and characterization of a parietal endoderm-like cell line derived from Engelbreth-Holm-Swarm tumor (EHSPEL), a possible resource for an engineered basement membrane matrix. Matrix Biol. 2004, 23, 47–62. [Google Scholar] [CrossRef]
VEGF 1/VEGFR 2 Targeting Therapeutic Agent | Therapeutic Strategy | Cancer Type | Clinical Trial Reference (Phase) |
---|---|---|---|
Bevacizumab (Apatinib) | Bevacizumab (anti-VEGF) in a chemotherapeutic cocktail with 5-Fu, Folinic acid, Panitumumab and intra-arterial vs. intravenous Oxaliplatin | Colorectal neoplasms | NCT02885753 (3) |
Cisplatin with Etoposide vs. Cisplatin, Etoposide and Bevacizumab | Small cell lung cancer | NCT03100955 (3) | |
Bevacizumab vs. placebo | Thyroid cancer | NCT03048877 (3) | |
Bevacizumab as second line treatment | Intrahepatic Cholangiocarcinoma | NCT03251443 (3) | |
LY01008 and Bevacizumab | LY01008 (anti-VEGF antibody) with Carboplatin/Paclitaxel vs. Bevacizumab with Carboplatin/Paclitaxel | Non-small cell lung cancer | NCT03533127 (3) |
Cediranib | Olaparib (PARP inhibitor) with Cediranib (VEGF-A inhibitor) or Olaparib alone | Ovarian cancer | NCT03278717 (3) |
Ramucirumab (LY3009806) | Ramucirumab (anti-VEGFR) with Paclitaxel vs. Placebo with Paclitaxel | Gastric adenocarcinoma | NCT02898077 (3) |
Aflibercept | Injection of Aflibercept (anti-VEGF) vs. placebo injection | Ocular melanoma | NCT03172299 (3) |
Everolimus (RAD001) | Everolimus (m-TOR inhibitor) alone | Renal cell carcinoma | NCT01206764 (4) |
Therapeutic Agent | Therapeutic Agent Description | Cancer Type | Clinical Trial Reference (Phase) |
---|---|---|---|
Pexidartinib (PLX3397) | CSF-1R 1 inhibitor | Advanced solid tumors Giant cell tumor Melanoma Pancreatic/Colorectal cancer Gastrointestinal stromal cancer Advanced solid tumors Gastric cancer | NCT02734433 (-) NCT02371369 (3) NCT02975700 (1/2) NCT02777710 (1) NCT03158103 (1) NCT01525602 (1) NCT03694977 (2) |
ARRY-382 | CSF-1R inhibitor | Advanced solid tumors | NCT02880371 (2) |
BLZ945 | CSF-1R inhibitor | Advanced solid tumors | NCT02829723 (1/2) |
JNJ-40346527 | CSF-1R inhibitor | Prostate cancer | NCT03177460 (1) |
Emactuzumab | CSF-1R antibody | Squamous cell carcinoma | NCT03708224 (2) |
DCC-3014 | CSF-1R inhibitor | Advanced malignant neoplasm | NCT03069469 (1) |
Chiauranib | Tyrosine kinase inhibitor | Ovarian cancer Small Cell Lung cancer Hepatocellular carcinoma | NCT03166891 (1) NCT03216343 (1) NCT03245190 (1) |
IMC-CS4 (LY3022855) | CSF-1R blocking agent | Pancreatic cancer Melanoma | NCT03153410 (1) NCT03101254 (1/2) |
Cabiralizumab (FPA008) | CSF-1R antibody | Pancreatic cancer Melanoma/Non-small cell lung cancer/Renal cell carcinoma Resectable biliary tract cancer | NCT03697564 (2) NCT03502330 (1) NCT03768531 (2) |
SNDX-6352 (UCB6352) | CSF-1R antibody | Advanced malignant neoplasm | NCT03238027 (1) |
PD 0360324 | CSF-1 antibody | Ovarian cancer | NCT02948101 (2) |
Nilotinib | Tyrosine kinase inhibitor | Malignant solid neoplasms Soft tissue sarcoma | NCT02029001 (2) NCT03784014 (3) |
Lacnotuzumab (MCS110) | CSF-1 antibody | Melanoma | NCT03455764 (1/2) |
Therapeutic Agent | Therapeutic Strategy | Cancer Type | Clinical Trial Reference (Phase) |
---|---|---|---|
Anakinra (Kineret) | Combined with Nab-paclitaxel, Gemcitabine, Cisplatin | Pancreatic cancer | NCT02550327 (1) |
Alone | Multiple myeloma | NCT03233776 (2) | |
Canakinumab (Ilaris) | Alone | 1 NSCLC | NCT03447769 (3) |
Chemotherapeutic cocktail with or without Canakinumab | NSCLC | NCT03631199 (3) | |
Possible use of Canakinumab with Spartalizumab and LAG525 | 2 TNBC | NCT03742349 (1) | |
Docetaxel with Canakinumab vs. Docetaxel with placebo | NSCLC | NCT03626545 (3) | |
Possible use with PDR001 | Colorectal cancer/TNBC/NSCLC | NCT02900664 (1) | |
Possible use with PDR001, cisplatin, pemetrexed and carboplatin | NSCLC | NCT03064854 (1) | |
Possible use with PDR001 | Melanoma | NCT03484923 (2) |
Therapeutic Strategy | Cancer Type | Phase | Clinical Trial Reference |
---|---|---|---|
HLX10 (anti-PD-1 1) + HLX04 (anti-VEGF 2) | Solid tumor | 1 | NCT03757936 |
SHR-1210 (anti-PD-1) with Bevacizumab (anti-VEGFR) | Gastric and hepatocellular cancer | 1/2 | NCT02942329 |
Atezolizumab (anti-PD-L1) with Bevacizumab (anti-VEGF) | Digestive, respiratory and intrathoracic organs tumors | 2 | NCT03074513 |
Atezolizumab (PD-L1 inhibitor), Bevacizumab (anti-VEGF) and Cobimetinib (MEK 3 inhibitor) | Ovarian and fallopian tube cancer and peritoneal carcinoma | 2 | NCT03363867 |
PLD 4 with Atezolizumab (PD-L1 inhibitor) vs. PLD with Bevacizumab (anti-VEGF) and Atezolizumab vs. PLD with Bevacizumab | Ovarian, fallopian tube and peritoneal carcinoma | 2/3 | NCT02839707 |
Sintilimab (anti-PD-1) with IBI305 (anti-VEGF), Pemetrexed and Cisplatin vs. Sintilimab with IBI305 and Pemetrexed vs. Pemetrexed and Cisplatin | Non-squamous non-small cell lung cancer | 3 | NCT03802240 |
Bevacizumab (anti-VEGF) with Carboplatin and Pemetrexed vs. Bevacizumab with Atezolizumab (anti-PD-1), Carboplatin and Pemetrexed | Pleural mesothelioma malignant advanced | 3 | NCT03762018 |
Tyrosine Kinase Inhibitor | Inhibited Tyrosine Kinases | Therapeutic Strategy/Objective | Cancer Type | Phase | Clinical Trial Reference |
---|---|---|---|---|---|
Sitravatinib (MGCD516) | c-Met, AXL, MER, VEGFR 1, PDGFR 2, DDR2, TRK 3, Eph 4 | Dosage and clinical activity of Sitravatinib | Advanced cancer | 1/1b | NCT02219711 |
Sitravatinib with Nivolumab (Opdivo, anti-PD-1 5) | Renal cell cancer | 1/2 | NCT03015740 | ||
Axitinib (AG-013736) | VEGFR1-3, c-KIT, PDGFR | Avelumab (anti-PD-1) with Axitinib | Non-small cell lung or urothelial cancer | 2 | NCT03472560 |
Sandostatin LAR with Axitinib vs. with placebo | Neuroendocrine tumors | 2/3 | NCT01744249 | ||
Cabozantinib | c-Met, VEGFR | Nivolumab (anti-PD-1) vs. Nivolumab with Cabozantinib | Renal cell carcinoma | 3 | NCT03793166 |
Lenvatinib | VEGFR1-3 | Lenvatinib with Pembrolizumab (anti-PD-1) vs. Paclitaxel or Doxorubicin | Endometrial neoplasms | 3 | NCT03517449 |
Culture Model | Composition | Major Advantages | Major Disadvantages | References |
---|---|---|---|---|
Tumor tissue explants | Tumor collected from a biopsy and placed on a collagen matrix | Maintenance of tumor architecture | Difficulty on maintaining the culture for more than 3 weeks | Reviewed in [183,189,190,191,192] |
Organoid cultures from tissue explants | Long-lasting culture | Poorly resembles TME 1 and disease progression | ||
“Tumor on a chip” | co-cultures of tumor cells with other cell types to organs | TME 1 reproduction with the movement of biological fluids | Size limited | Reviewed in [193,194,195,196,197,198,199,200] |
Multicellular Tumor Spheroids (MCTS) | Spheroids composed by mono- or co-culture aggregates | TME 1 reproduction | Fail in reproducing ECM architecture | Reviewed in [184,189,191,192,201] |
Spheroids composed by mono- or co-cultures on a scaffold | TME 1 reproduction ECM 2 architecture reproduction | Low reproducibility Cost |
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Roma-Rodrigues, C.; Mendes, R.; Baptista, P.V.; Fernandes, A.R. Targeting Tumor Microenvironment for Cancer Therapy. Int. J. Mol. Sci. 2019, 20, 840. https://doi.org/10.3390/ijms20040840
Roma-Rodrigues C, Mendes R, Baptista PV, Fernandes AR. Targeting Tumor Microenvironment for Cancer Therapy. International Journal of Molecular Sciences. 2019; 20(4):840. https://doi.org/10.3390/ijms20040840
Chicago/Turabian StyleRoma-Rodrigues, Catarina, Rita Mendes, Pedro V. Baptista, and Alexandra R. Fernandes. 2019. "Targeting Tumor Microenvironment for Cancer Therapy" International Journal of Molecular Sciences 20, no. 4: 840. https://doi.org/10.3390/ijms20040840