Vaupel P. Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol. 2004;14:198–206.
Petrova V, Annicchiarico-Petruzzelli M, Melino G, Amelio I. The hypoxic tumour micro-environ-ment. Oncogenesis. 2018;7:10.
Lunt SJ, Fyles A, Hill RP, Milosevic M. Interstitial fluid pressure in tumors: therapeutic barrier and biomarker of angiogenesis. Future Oncol. 2008;4:793–802.
Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol. 2012;196:395–406.
Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol. 2013;31:2205–18.
Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.
Whatcott CJ, Han H, von Hoff DD. Orchestrating the tumor microenvironment to improve survival for patients with pancreatic cancer: normalization, not destruction. Cancer J. 2015;21:299–306.
Stylianopoulos T, Munn LL, Jain RK. Reengineering the physical microenvironment of tumors to improve drug delivery and efficacy: from mathematical modeling to bench to bedside. Trends Cancer. 2018;4:292–319.
Brossa A, Buono L, Fallo S, Fiorio Pla A, Munaron L, Bussolati B. Alternative strategies to inhibit tumor vascularization. Int J Mol Sci. 2019;20:E6180.
Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315:1650–9.
Neesse A, Bauer CA, Öhlund D, Lauth M, Buchholz M, Michl P, Tuveson DA, Gress TM. Stromal biology and therapy in pancreatic cancer: ready for clinical translation? Gut. 2019;68:159–71.
Nia HT, Liu H, Seano G, Datta M, Jones D, Rahbari N, Incio J, Chauhan VP, Jung K, Martin JD, et al. Solid stress and elastic energy as measures of tumour mechanopathology. Nat Biomed Eng. 2016;1:0004.
Kalli M, Papageorgis P, Gkretsi V, Stylianopoulos T. Solid stress facilitates fibroblasts activation to promote pancreatic cancer cell migration. Ann Biomed Eng. 2018;46:657–69.
DuFort CC, DelGiorno KE, Carlson MA, Osgood RJ, Zhao C, Huang Z, Thompson CB, Connor RJ, Thanos CD, Scott Brockenbrough J, et al. Interstitial pressure in pancreatic ductal adenocarcinoma is dominated by a gel-fluid phase. Biophys J. 2016;110:2106–19.
Heldin CH, Rubin K, Pietras K, Östman A. High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer. 2004;4:806–13.
Gulliksrud K, Galappathi K, Rofstad EK. Interstitial fluid pressure and vascularity of intra-dermal and intramuscular human tumor xenografts. Int J Radiat Oncol Biol Phys. 2011;80:258–64.
Rofstad EK, Ruud EB, Mathiesen B, Galappathi K. Associations between radiocurability and interstitial fluid pressure in human tumor xenografts without hypoxic tissue. Clin Cancer Res. 2010;16:936–45.
Jain RK. Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastasis Rev. 1990;9:253–66.
Bouzin C, Feron O. Targeting tumor stroma and exploiting mature tumor vasculature to improve anti-cancer drug delivery. Drug Resist Uptake. 2007;10:109–20.
Cirri P, Chiarugi P. Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev. 2012;31:195–208.
Anttila MA, Tammi RH, Tammi MI, Syrjänen KJ, Saarikoski SV, Kosma VM. High levels of stromal hyaluronan predict poor disease outcome in epithelial ovarian cancer. Cancer Res. 2000;60:150–5.
Elahi-Gedwillo KY, Carlson M, Zettervall J, Provenzano PP. Antifibrotic therapy disrupts stromal barriers and modulates the immune landscape in pancreatic ductal adenocarcinoma. Cancer Res. 2019;79:372–86.
Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010;31:220–7.
Barron DA, Rowley DR. The reactive stroma microenvironment and prostate cancer progres-sion. Endocr Relat Cancer. 2012;19:R187–204.
Lunardi S, Muschel RJ, Brunner TB. The stromal compartments in pancreatic cancer: are there any therapeutic targets? Cancer Lett. 2014;343:147–55.
Jain RK. Transport of molecules in the tumor interstitium: a review. Cancer Res. 1987;47:3039–51.
Minchinton AI, Tannock IF. Drug penetration in solid tumors. Nat Rev Cancer. 2006;6:583–92.
Choi J, Credit K, Henderson K, Deverkadra R, He Z, Wiig H, Vanpelt H, Flessner MF. Intraperitoneal immunotherapy for metastatic ovarian carcinoma: resistance of intratumoral collagen to antibody penetration. Clin Cancer Res. 2006;12:1906–12.
Erikson A, Andersen HN, Naess SN, Sikorski P, de Davies CL. Physical and chemical modifications of collagen gels: impact on diffusion. Biopolymers. 2008;89:135–43.
Wiig H, Gyenge C, Iversen PO, Gullberg D, Tenstad O. The role of the extracellular matrix in tissue distribution of macromolecules in normal and pathological tissues: potential therapeutic consequences. Microcirculation. 2008;15:283–96.
Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol. 2010;7:653–64.
Sironen RK, Tammi M, Tammi R, Auvinen PK, Antilla M, Kosma VM. Hyaluronan in human malignancies. Exp Cell Res. 2011;317:383–91.
Voutouri C, Polydorou C, Papageorgis P, Gkretsi V, Stylianopoulos T. Hyaluronan-derived swelling of solid tumors, the contribution of collagen and cancer cells, and implications for cancer therapy. Neoplasia. 2016;18:732–41.
Dolor A, Szoka FC Jr. Digesting a path forward: the utility of collagenase tumor treatment for improved drug delivery. Mol Pharm. 2018;15:2069–83.
Brown E, McKee T, di Tomaso E, Pluen A, Seed B, Boucher Y, Jain RK. Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation. Nat Med. 2003;6:796–800.
McKee TD, Grandi P, Mok W, Alexandrakis G, Insin N, Zimmer JP, Bawendi MG, Boucher Y, Breakefield XO, Jain RK. Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector. Cancer Res. 2006;66:2509–13.
Kim JH, Lee YS, Kim H, Huang JH, Yoon AR, Yun CO. Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy. J Natl Cancer Inst. 2006;98:1482–93.
Ganesh S, Gonzalez Edick M, Idamakanti N, Abramova M, Vanroey M, Robinson M, Yun CO, Jooss K. Relaxin-expressing, fiber chimeric oncolytic adenovirus prolongs survival of tumor-bearing mice. Cancer Res. 2007;67:4399–407.
Masterson R, Hewitson TD, Kelynak K, Martic M, Parry L, Bathgate R, Darby I, Becjer G. Relaxin down-regulates renal fibroblast function and promotes matrix remodelling in vitro. Nephrol Dial Transplant. 2004;19:544–52.
Eikenes L, Tari M, Tufto I, Bruland OS, de Davies CL. Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx) in human osteosarcoma xenografts. Br J Cancer. 2005;93:81–8.
de la Motte C, Nigro J, Vasanji A, Rho H, Kessler S, Bandyopadhyay S, Danese S, Fiocchi C, Stern R. Platelet-derived hyaluronidase 2 cleves hyaluronan into fragments that trigger monocyte-mediated production of proinflammatory cytokines. Am J Pathol. 2009;174:2254–64.
Thompson CB, Shepard HM, O’Connor PM, Kadhim S, Jiang P, Osgood RJ, Bookbinder LH, Li X, Sugarman BJ, Connor RJ, et al. Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models. Mol Cancer Ther. 2010;9:3052–64.
Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 2000;60:2497–503.
Goodman TT, Olive PL, Pun SH. Increased nanoparticle penetration in collagenase-treated multicellular spheroids. Int J Nanomedicine. 2007;2:265–74.
Mok W, Boucher Y, Jain RK. Matrix metalloproteinases-1 and -8 improve the distribution and efficacy of an oncolytic virus. Cancer Res. 2007;67:10664–8.
Magzoub M, Jin S, Verkman AS. Enhanced macromolecule diffusion deep in tumors after enzymatic digestion of extracellular matrix collagen and its associated proteoglycan decorin. FASEB J. 2008;22:276–84.
Eikenes L, Tufto I, Schnell EA, Bjørkøy A, de Davies CL. Effect of collagenase and hyaluronidase on free and anomalous diffusion in multicellular spheroids and xenografts. Anticancer Res. 2010;30:359–68.
Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, Feig C, Nakagawa T, Caldwell ME, Zecchini HI, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013;62:112–20.
Kohli AG, Kivimäe S, Tiffany MR, Szoka FC. Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan. J Control Release. 2014;191:105–14.
Zhang B, Jiang T, She X, Shen S, Wang S, Deng J, Shi W, Mei H, Hu Y, Pang Z, et al. Fibrin degradation by rtPA enhances the delivery of nanotherapeutics to A549 tumors in nude mice. Biomaterials. 2016;96:63–71.
Dong X, Liu HJ, Feng HY, Yang SC, Liu XL, Lai X, Lu Q, Lovell JF, Chen HZ, Fang C. Enhanced drug delivery by nanoscale integration of a nitric oxide donor to induce tumor collagen depletion. Nano Lett. 2019;19:997–1008.
Khawar IA, Kim JH, Kuh HJ. Improving drug delivery to solid tumors: priming the tumor microenvironment. J Control Release. 2015;201:78–89.
Cox TR, Erler JT. Fibrosis and cancer: partners in crime or opposing forces? Trends Cancer. 2016;2:279–82.
Jiang P, Li X, Thompson CB, Huang Z, Araiza F, Osgood R, Wei G, Feldmann M, Frost GI, Shepard HM. Effective targeting of the tumor microenvironment for cancer therapy. Anti-cancer Res. 2012;32:1203–12.
Singha NC, Nekoroski T, Zhao C, Symons R, Jiang P, Frost GI, Huang Z, Shepard HM. Tumor-associated hyaluronan limits efficacy of monoclonal antibody therapy. Mol Cancer Ther. 2015;14:523–32.
Shepard HM. Breaching the castle walls: hyaluronan depletion as a therapeutic approach to cancer therapy. Front Oncol. 2015;5:192.
Wong KM, Horton KJ, Coveler AR, Hingorani SR, Harris WP. Targeting the tumor stroma: the biology and clinical development of pegylated recombinant human hyaluronidase (PEGPH20). Curr Oncol Rep. 2017;19:47.
Infante JR, Korn RL, Rosen LS, LoRusso P, Dychter SS, Zhu J, Maneval DC, Jiang P, Shepard HM, Frost G, et al. Phase 1 trials of PEGylated recombinant human hyaluronidase PH20 in patients with advanced solid tumours. Br J Cancer. 2018;118:153–61.
Doherty GJ, Tempero M, Corrie PG. HALO-109-301: a phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer. Future Oncol. 2018;14:13–22.
Gourd E. PEGPH20 for metastatic pancreatic ductal adenocarcinoma. Lancet Oncol. 2018;19:e81.
Provenzano PP, Cuevas C, Chang AE, Goel VK, von Hoff DD, Hingorani SR. Enzy-matic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adeno-carcinoma. Cancer Cell. 2012;21:418–29.
Yu M, Tannock IF. Targeting tumor architecture to favor drug penetration: a new weapon to combat chemoresistance in pancreatic cancer. Cancer Cell. 2012;21:327–9.
Chauhan VP, Boucher Y, Ferrone CR, Roberge S, Martin JD, Stylianopoulos T, Bardeesy N, DePinho RA, Padera TP, Munn LL, et al. Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure. Cancer Cell. 2014;26:14–5.
Hingorani SR, Zheng L, Bullock AJ, Seery TE, Harris WP, Sigal DS, Braiteh F, Ritch PS, Zalupski MM, Bahary N, et al. HALO 202: randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2018;36:359–66.
ClinicalTrials.gov. A study of PEGylated recombinant human hyaluronidase in combination with nab-paclitaxel plus gemcitabine compared with placebo plus nab-paclitaxel and gemci-tabine in participants with hyaluronan-high stage IV previously untreated pancreatic ductal adenocarcinoma (NCT02715904). https://clinicaltrials.gov/ct2/show/NCT02715804. Accessed 3 Dec 2019.
Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009;139:891–906.
Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, Oyasu M, Mikels A, Vaysberg M, Ghermazien H, Wai C, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010;16:1009–17.
Baker AM, Bird D, Lang G, Cox TR, Erler JT. Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK. Oncogene. 2013;32:1863–8.
di Stefano V, Torsello B, Bianchi C, Cifola I, Mangano E, Bovo G, Cassina V, de Marco S, Corti R, Meregalli C, et al. Major action of endogenous lysyl oxidase in clear cell renal cell carcinoma progression and collagen stiffness revealed by primary cell cultures. Am J Pathol. 2016;186:2473–85.
Erler JT, Bennewith KL, Nicolau M, Dornhöfer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 2006;440:1222–6.
Sion AM, Figg WD. Lysyl oxidase (LOX) and hypoxia-induced metastases. Cancer Biol Ther. 2006;5:909–11.
Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the pre-metastatic niche. Cancer Cell. 2009;15:35–44.
Semenza GL. Molecular mechanisms mediating metastasis of hypoxic breast cancer cells. Trends Mol Med. 2012;18:534–43.
Wong CC, Tse AP, Huang YP, Zhu YT, Chiu DK, Lai RK, Au SL, Kai AK, Lee JM, Wei LL, et al. Lysyl oxidase-like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma. Hepatology. 2014;60:1645–58.
Fang M, Yuan J, Peng C, Li Y. Collagen as a double-edged sword in tumor progression. Tumour Biol. 2014;35:2871–82.
Chang J, Erler J. Hypoxia-mediated metastasis. Adv Exp Med Biol. 2014;772:55–81.
Cox TR, Rumney RM, Schoof EM, Perryman L, Høye AM, Agrawal A, Bird D, Latif NA, Forrest H, Evans HR, et al. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature. 2015;522:106–10.
Cox TR, Gartland A, Erler JT. Lysyl oxidase, a targetable secreted molecule involved in cancer metastasis. Cancer Res. 2016;76:188–92.
Rachman-Tzemah C, Zaffryar-Eilot S, Grossman M, Ribero D, Timaner M, Mäki JM, Myllyharju J, Bertolini F, Hershkovitz D, Sagi I, et al. Blocking surgically induced lysyl oxidase activity reduces the risk of lung metastases. Cell Rep. 2017;19:774–84.
Umezaki N, Nakagawa S, Yamashita YI, Kitano Y, Arima K, Miyata T, Hiyoshi Y, Okabe H, Nitta H, Hayashi H, et al. Lysyl oxidase induces epithelial-mesenchymal transition and pre-dicts intrahepatic metastasis of hepatocellular carcinoma. Cancer Sci. 2019;110:2033–43.
Miller BW, Morton JP, Pinese M, Saturno G, Jamieson NB, McGhee E, Timpson P, Leach J, McGarry L, Shanks E, et al. Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol Med. 2015;7:1063–76.
ANZCTR (Australian New Zealand Clinical Trials Registry). A single ascending dose and multiple ascending dose phase 1 study of PXS-5505A administered orally in healthy adult males. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377011. Accessed 3 Dec 2019.
Pharmaxis Ltd. Pharmaxis cancer drug progressing in clinic. Oral pan-LOX inhibitor now in phase 1b following positive phase 1a data. Press release 24 Oct 2019.
Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A, et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med. 2008;14:518–27.
Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev Cell. 2010;18:884–901.
Borriello L, Nakata R, Sheard MA, Fernandez GE, Sposto R, Malvar J, Blavier L, Shimada H, Asgharzadeh S, Seeger RC, et al. Cancer-associated fibroblasts share characteristics and protumorigenic activity with mesenchymal stromal cells. Cancer Res. 2017;77:5142–57.
Kim DE, Procopio MG, Ghosh S, Jo SH, Goruppi S, Magliozzi F, Bordignon P, Neel V, Angelino P, Dotto GP. Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation. J Exp Med. 2017;214:2349–68.
Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25:719–34.
Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–98.
Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R. Discovery of endothelial to mesen-chymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 2007;67:10123–8.
Mishra PJ, Mishra PJ, Humeniuk R, Medina DJ, Alexe G, Mesirov JP, Ganesan S, Glod JW, Banerjee D. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res. 2008;68:4331–9.
Paunescu V, Bojin FM, Tatu CA, Gavriliuc OI, Rosca A, Gruia AT, Tanasie G, Bunu C, Crisnic D, Gherghiceanu M, et al. Tumour-associated fibroblasts and mesenchymal stem cells: more similarities than differences. J Cell Mol Med. 2011;15:635–46.
Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, Baik GH, Shibata W, Diprete B, Betz KS, et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell. 2011;19:257–72.
Vicent S, Sayles LC, Vaka D, Khatri P, Gevaert O, Chen R, Zheng Y, Gillespie AK, Clarke N, Xu Y, et al. Cross-species functional analysis of cancer-associated fibroblasts identifies a critical role for CLCF1 and IL-6 in non-small cell lung cancer in vivo. Cancer Res. 2012;72:5744–56.
Kidd S, Spaeth E, Watson K, Burks J, Lu H, Klopp A, Andreeff M, Marini FC. Origins of the tumor microenvironment: quantitative assessment of adipose-derived and bone marrow-derived stroma. PLoS ONE. 2012;7:e30563.
Garcia J, Sandi MJ, Cordelier P, Binétruy B, Pouysségur J, Iovanna JL, Tournaire R. Tie1 deficiency induces endothelial-mesenchymal transition. EMBO Rep. 2012;13:431–9.
Mathew E, Brannon AL, del Vecchio A, Garcia PE, Penny MK, Kane KT, Vinta A, Buckanovich RJ, di Magliano MP. Mesenchymal stem cells promote pancreatic tumor growth by inducing alternative polarization of macrophages. Neoplasia. 2016;18:142–51.
Waghray M, Yalamanchili M, Dziubinski M, Zeinali M, Erkkinen M, Yang H, Schradle KA, Urs S, Pasca di Magliano M, Welling TH, et al. GM-CSF mediates mesenchymal-epithelial cross-talk in pancreatic cancer. Cancer Discov. 2016;6:886–99.
Neesse A, Frese KK, Bapiro TE, Nakagawa T, Sternlicht MD, Seeley TW, Pilarsky C, Jodrell DI, Spong SM, Tuveson DA. CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer. Proc Natl Acad Sci USA. 2013;110:12325–30.
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;106:134–42.
Duluc C, Moatassim-Billah S, Chalabi-Dchar M, Perraud A, Samain R, Breibach F, Gayral M, Cordelier P, Delisle MB, Bousquet-Dubouch MP, et al. Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pan-creatic tumour chemoresistance. EMBO Mol Med. 2015;7:735–53.
Chen B, Wang Z, Sun J, Song Q, He B, Zhang H, Wang X, Dai W, Zhang Q. A tenascin C targeted nanoliposome with navitoclax for specifically eradicating of cancer-associated fibroblasts. Nanomedicine. 2016;12:131–41.
Jiang GM, Xu W, Du J, Zhang KS, Zhang QG, Wang XW, Liu ZG, Liu SQ, Xie WY, Liu HF, et al. The application of the fibroblast activation protein α-targeted immunotherapy strategy. Oncotarget. 2016;7:33472–82.
Gascard P, Tlsty TD. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev. 2016;30:1002–19.
Endo S, Nakata K, Ohuchida K, Takesue S, Nakayama H, Abe T, Koikawa K, Okumura T, Sada M, Horioka K, et al. Autophagy is required for activation of pancreatic stellate cells, associated with pancreatic cancer progression and promotes growth of pancreatic tumors in mice. Gastroenterology. 2017;152:1492–506.
Zhen Z, Tang W, Wang M, Zhou S, Wang H, Wu Z, Hao Z, Li Z, Liu L, Xie J. Protein nanocage mediated fibroblast-activation protein targeted photoimmunotherapy to enhance cytotoxic T cell infiltration and tumor control. Nano Lett. 2017;17:862–9.
Dauer P, Zhao X, Gupta VK, Sharma N, Kesh K, Gnamlin P, Dudeja V, Vickers SM, Banerjee S, Saluja A. Inactivation of cancer-associated-fibroblasts disrupts oncogenic signaling in pancreatic cancer cells and promotes its regression. Cancer Res. 2018;78:1321–33.
Djurec M, Graña O, Lee A, Troulé K, Espinet E, Cabras L, Navas C, Blasco MT, Martín-Díaz L, Burdiel M, et al. Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors. Proc Natl Acad Sci USA. 2018;115:E1147–56.
Chronopoulos A, Robinson B, Sarper M, Cortes E, Auernheimer V, Lachowski D, Attwood S, Garcia R, Ghassemi S, Fabry B, et al. ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion. Nat Commun. 2016;7:12630.
ClinicalTrials.gov. Stromal targeting for pancreatic cancer (STARPAC, NCT03307148). https://clinicaltrials.gov/ct2/show/NCT03307148. Accessed 3 Dec 2019.
North B, Kocher HM, Sasieni P. A new pragmatic design for dose escalation in phase 1 clinical trials using an adaptive continual reassessment method. BMC Cancer. 2019;19:632.
Fabregat I, Fernando J, Mainez J, Sancho P. TGF-beta signaling in cancer treatment. Curr Pharm Des. 2014;20:2934–47.
Seoane J, Gomis RR. TGF-β family signaling in tumor suppression and cancer progression. Cold Spring Harb Perspect Biol. 2017;9:a022277.
Colak S, ten Dijke P. Targeting TGF-β signaling in cancer. Trends Cancer. 2017;3:56–71.
Skoda AM, Simovic D, Karin V, Kardum V, Vranic S, Serman L. The role of the Hedgehog signaling pathway in cancer: a comprehensive review. Bosn J Basic Med Sci. 2018;18:8–20.
Carballo GB, Honorato JR, de Lopes GPF, Spohr TCLSE. A highlight on Sonic hedgehog pathway. Cell Commun Signal. 2018;16:11.
Krishnamurthy N, Kurzrock R. Targeting the Wnt/beta-catenin pathway in cancer: update on effectors and inhibitors. Cancer Treat Rev. 2018;62:50–60.
Salaritabar A, Berindan-Neagoe I, Darvish B, Hadjiakhoondi F, Manayi A, Devi KP, Barreca D, Orhan IE, Süntar I, Faroogi AA, et al. Targeting Hedgehog signaling pathway: paving the road for cancer therapy. Pharmocol Res. 2019;141:466–80.
Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci USA. 2011;108:2909–14.
Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, et al. Angiotensin inhibition enhances drug delivery and poten-tiates chemotherapy by decompressing tumour blood vessels. Nat Commun. 2013;4:2516.
Murphy JE, Wo JY, Ryan DP, Clark JW, Jiang W, Yeap BY, Drapek LC, Ly L, Baglini CV, Blaszkowsky LS, et al. Total neoadjuvant therapy with FOLFIRINOX in combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: a phase 2 clinical trial. JAMA Oncol. 2019;5:1020–7.
Suker M, Beumer BR, Sadot E, Marthey L, Faris JE, Mellon EA, El-Rayes BF, Wang-Gillam A, Lacy J, Hosein PJ, et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol. 2016;17:801–10.
ClinicalTrials.gov. Losartan and nivolumab in combination with FOLFIRINOX and SBRT in localized pancreatic cancer (NCT03563248). https://clinicaltrials.gov/ct2/show/NCT03563248. Accessed 5 Dec 2019.
Zion O, Genin O, Kawada N, Yoshizato K, Roffe S, Nagler A, Iovanna JL, Halevy O, Pines M. Inhibition of transforming growth factor beta signaling by halofuginone as a modality for pancreas fibrosis prevention. Pancreas. 2009;38:427–35.
Spector I, Honig H, Kawada N, Nagler A, Genin O, Pines M. Inhibition of pancreatic stellate cell activation by halofuginone prevents pancreatic xenograft tumor development. Pancreas. 2010;39:1008–15.
Nelson EF, Huang CW, Ewel JM, Chang AA, Yuan C. Halofuginone down-regulates Smad3 expression and inhibits the TGFbeta-induced expression of fibrotic markers in human corneal fibroblasts. Mol Vis. 2012;18:479–87.
de Jonge MJA, Dumez H, Verweij J, Yarkoni S, Snyder D, Lacombe D, Marréaud S, Yama-guchi T, Punt CJ, van Oosterom A, et al. Phase I and pharmacokinetic study of halofuginone, an oral quinazolinone derivative in patients with advanced solid tumours. Eur J Cancer. 2006;42:1768–74.
Rubin LL, de Sauvage FJ. Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov. 2006;5:1026–33.
Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, Marshall D, Fu L, Januario T, Kallop D, et al. A paracrine requirement for hedgehog signalling in cancer. Nature. 2008;455:406–10.
Tian H, Callahan CA, DuPree KJ, Darbonne WC, Ahn CP, Scales SJ, de Sauvage FJ. Hedge-hog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci USA. 2009;106:4254–9.
Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell MA, Allard D, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324:1457–61.
Kim EJ, Sahai V, Abel EV, Griffith KA, Greenson JK, Takebe N, Khan GN, Blau JL, Craig R, Balis UG, et al. Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma. Clin Cancer Res. 2014;20:5937–45.
Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, et al. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015;33:4284–92.
Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, Becerra CP, Tattersall IW, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25:735–47.
Shin K, Lim A, Zhao C, Sahoo D, Pan Y, Spiekerkoetter E, Liao JC, Beachy PA. Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell. 2014;26:521–33.
Gerling M, Büller NV, Kirn LM, Joost S, Frings O, Englert B, Bergström Å, Kuiper RV, Blaas L, Wielenga MC, et al. Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth. Nat Commun. 2016;7:12321.
Yang Z, Peng YC, Gopalan A, Gao D, Chen Y, Joyner AL. Stromal hedgehog signaling maintains smooth muscle and hampers micro-invasive prostate cancer. Dis Model Mech. 2017;10:39–52.
Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, Collisson EA, Connor F, van Dyke T, Kozlov S, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014;159:80–93.
Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, Nywening TM, Hawkins WG, Shapiro IM, Weaver DT, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22:851–60.
ClinicalTrials.gov. Defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer (NCT02546531). https://clinicaltrials.gov/ct2/show/NCT02546531. Accessed 9 Dec 2019.
ClinicalTrials.gov. Study of FAK (defactinib) and PD-1 (pembrolizumab) inhibition in advanced solid malignancies (FAK-PD1). https://clinicaltrials.gov/ct2/show/study/NCT02758587. Accessed 9 Dec 2019.
Torres S, Bartolomé RA, Mendes M, Barderas R, Fernandez-Aceñero MJ, Peláez-García A, Peña C, Lopez-Lucendo M, Villar-Vázquez R, de Herreros AG, et al. Proteome profiling of cancer-associated fibroblasts identifies novel proinflammatory signatures and prognostic markers for colorectal cancer. Clin Cancer Res. 2013;19:6006–19.
Hanley CJ, Noble F, Ward M, Bullock M, Drifka C, Mellone M, Manousopoulou A, Johnston HE, Hayden A, Thirdborough S, et al. A subset of myofibroblastic cancer-associated fibro-blasts regulate collagen fiber elongation, which is prognostic in multiple cancers. Oncotarget. 2016;7:6159–74.
Öhlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, Corbo V, Oni TE, Hearn SA, Lee EJ, et al. Distinct populations of inflammatory fibroblasts and myofibro-blasts in pancreatic cancer. J Exp Med. 2017;214:579–96.
Öhlund D, Elyada E, Tuveson D. Fibroblast heterogeneity in the cancer wound. J Exp Med. 2014;211:1503–23.
Vennin C, Murphy KJ, Morton JP, Cox TR, Pajic M, Timpson P. Reshaping the tumor stroma for treatment of pancreatic cancer. Gastroenterology. 2018;154:820–38.
Wilop S, von Hobe S, Crysandt M, Esser A, Osieka R, Jost E. Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy. J Cancer Res Clin Oncol. 2009;135:1429–35.
Keizman D, Huang P, Eisenberger MA, Pili R, Kim JJ, Antonarakis ES, Hammers H, Carducci MA. Angiotensin system inhibitors and outcome of sunitinib treatment in patients with metastatic renal cell carcinoma: a retrospective examination. Eur J Cancer. 2011;47:1955–61.
Pelullo M, Zema S, Nardozza F, Checquolo S, Screpanti I, Bellavia D. Wnt, Notch, and TGF-β pathways impinge on Hedgehog signaling complexity: an open window on cancer. Front Genet. 2019;10:711.