Skip to main content

Advertisement

SpringerLink
Log in

Restriction of drug transport by the tumor environment

  • Review
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

As in the systemic treatment of any disease, it is crucial for anti-cancer drugs to reach their target at a sufficient that is a therapeutically effective dose. However, unlike normal organs, solid tumors have a tendency to be undersupplied and hypoxic. This not only leads to insufficient supply of oxygen and nutrients but also to inefficient transport of drugs into tumors. As a consequence, administered doses have to be raised, resulting in increased side effects and often premature termination of treatment. A better understanding of the mechanisms that hamper transport of drugs into tumors could lead to the development of auxiliary strategies aimed at increasing tumor drug delivery and accumulation and thereby improving the efficacy of anti-cancer drugs at our disposal. The tumor microenvironment (TME), i.e., its vasculature, stroma, extracellular matrix and immune environment affect the transport of drugs to the tumor and their distribution within the tumor tissue in various ways. In this review we will highlight the current research regarding the cellular and molecular mechanisms that remain as an obstacle towards an effective cancer therapy, and also focus on the various strategies to alter the TME to increase tumor drug exposure and thereby treatment efficacy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Afik R, Zigmond E, Vugman M, Klepfish M, Shimshoni E, Pasmanik-Chor M, Shenoy A, Bassat E, Halpern Z, Geiger T, Sagi I, Varol C (2016) Tumor macrophages are pivotal constructors of tumor collagenous matrix. J Exp Med 213(11):2315–2331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anampa J, Makower D, Sparano JA (2015) Progress in adjuvant chemotherapy for breast cancer: an overview. BMC Med 13:195

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Arap W, Pasqualini R, Ruoslahti E (1998) Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279(5349):377–380

    Article  CAS  PubMed  Google Scholar 

  • Arjaans M, Oude Munnink TH, Oosting SF, Terwisscha AG, van Scheltinga JA, Gietema ET, Garbacik H, Timmer-Bosscha MN, Lub-de Hooge CP, Schroder, de Vries EG (2013) Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake. Cancer Res 73(11):3347–3355

    Article  CAS  PubMed  Google Scholar 

  • Bagordakis E, Sawazaki-Calone I, Macedo CC, Carnielli CM, de Oliveira CE, Rodrigues PC, Rangel AL, Dos Santos JN, Risteli J, Graner E, Salo T, Paes Leme AF, Coletta RD (2016) Secretome profiling of oral squamous cell carcinoma-associated fibroblasts reveals organization and disassembly of extracellular matrix and collagen metabolic process signatures. Tumour Biol 37(7):9045–9057

    Article  CAS  PubMed  Google Scholar 

  • Baish JW, Gazit Y, Berk DA, Nozue M, Baxter LT, Jain RK (1996) Role of tumor vascular architecture in nutrient and drug delivery: an invasion percolation-based network model. Microvasc Res 51(3):327–346

    Article  CAS  PubMed  Google Scholar 

  • Balluff B, Hanselmann M, Heeren RM (2017) Mass spectrometry imaging for the investigation of intratumor heterogeneity. Adv Cancer Res 134:201–230

    Article  CAS  PubMed  Google Scholar 

  • Barcellos-de-Souza P, Comito G, Pons-Segura C, Taddei ML, Gori V, Becherucci V, Bambi F, Margheri F, Laurenzana A, Del Rosso M, Chiarugi P (2016) Mesenchymal stem cells are recruited and activated into carcinoma-associated fibroblasts by prostate cancer microenvironment-derived TGF-beta1. Stem Cells 34(10):2536–2547

    Article  CAS  PubMed  Google Scholar 

  • Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1):83–95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benevides L, da Fonseca DM, Donate PB, Tiezzi DG, De Carvalho DD, de Andrade JM, Martins GA, Silva JS (2015) IL17 promotes mammary tumor progression by changing the behavior of tumor cells and eliciting tumorigenic neutrophils recruitment. Cancer Res 75(18):3788–3799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borriello L, Nakata R, Sheard MA, Fernandez GE, Sposto R, Malvar J, Blavier L, Shimada H, Asgharzadeh S, Seeger RC, DeClerck YA (2017) Cancer-associated fibroblasts share characteristics and protumorigenic activity with mesenchymal stromal cells. Cancer Res 77(18):5142–5157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brandau S (2013) The dichotomy of neutrophil granulocytes in cancer. Semin Cancer Biol 23(3):139–140

    Article  CAS  PubMed  Google Scholar 

  • Bussink J, Kaanders JH, Rijken PF, Martindale CA, van der Kogel AJ (1998) Multiparameter analysis of vasculature, perfusion and proliferation in human tumour xenografts. Br J Cancer 77(1):57–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caino MC, Chae YC, Vaira V, Ferrero S, Nosotti M, Martin NM, Weeraratna A, O’Connell M, Jernigan D, Fatatis A, Languino LR, Bosari S, Altieri DC (2013) Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells. J Clin Investig 123(7):2907–2920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carlson MR, Pope WB, Horvath S, Braunstein JG, Nghiemphu P, Tso CL, Mellinghoff I, Lai A, Liau LM, Mischel PS, Dong J, Nelson SF, Cloughesy TF (2007) Relationship between survival and edema in malignant gliomas: role of vascular endothelial growth factor and neuronal pentraxin 2. Clin Cancer Res 13(9):2592–2598

    Article  CAS  PubMed  Google Scholar 

  • Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, Popovic Z, Huang P, Bawendi MG, Boucher Y, Jain RK (2013) Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun 4:2516

    Article  PubMed  CAS  Google Scholar 

  • Che Y, Wang J, Li Y, Lu Z, Huang J, Sun S, Mao S, Lei Y, Zang R, Sun N, He J (2018) Cisplatin-activated PAI-1 secretion in the cancer-associated fibroblasts with paracrine effects promoting esophageal squamous cell carcinoma progression and causing chemoresistance. Cell Death Dis 9(7):759

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen Y, Zhang W, Huang Y, Gao F, Fang X (2016) In vivo biodistribution and anti-tumor efficacy evaluation of doxorubicin and paclitaxel-loaded pluronic micelles decorated with c(RGDyK) peptide. PLoS One 11(3):e0149952

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Claes A, Wesseling P, Jeuken J, Maass C, Heerschap A, Leenders WP (2008) Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Mol Cancer Ther 7(1):71–78

    Article  CAS  PubMed  Google Scholar 

  • Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS, Verstegen NJM, Ciampricotti M, Hawinkels L, Jonkers J, de Visser KE (2015) IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522(7556):345–348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, Clouthier SG, Wicha MS (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci USA 109(8):2784–2789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Connell JJ, Sugihara Y, Torok S, Dome B, Tovari J, Fehniger TE, Marko-Varga G, Vegvari A (2015) Localization of sunitinib in in vivo animal and in vitro experimental models by MALDI mass spectrometry imaging. Anal Bioanal Chem 407(8):2245–2253

    Article  CAS  PubMed  Google Scholar 

  • Conti JA, Kendall TJ, Bateman A, Armstrong TA, Papa-Adams A, Xu Q, Packham G, Primrose JN, Benyon RC, Iredale JP (2008) The desmoplastic reaction surrounding hepatic colorectal adenocarcinoma metastases aids tumor growth and survival via alphav integrin ligation. Clin Cancer Res 14(20):6405–6413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Curry CL, Reed LL, Golde TE, Miele L, Nickoloff BJ, Foreman KE (2005) Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi’s sarcoma tumor cells. Oncogene 24(42):6333–6344

    Article  CAS  PubMed  Google Scholar 

  • Dellian M, Witwer BP, Salehi HA, Yuan F, Jain RK (1996) Quantitation and physiological characterization of angiogenic vessels in mice: effect of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and host microenvironment. Am J Pathol 149(1):59–71

    CAS  PubMed  PubMed Central  Google Scholar 

  • DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA, Rugo HS, Hwang ES, Jirstrom K, West BL, Coussens LM (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1(1):54–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK (2011) Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci USA 108(7):2909–2914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dreher MR, Liu W, Michelich CR, Dewhirst MW, Yuan F, Chilkoti A (2006) Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst 98(5):335–344

    Article  CAS  PubMed  Google Scholar 

  • Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, Song H, Vandenberg S, Johnson RS, Werb Z, Bergers G (2008) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13(3):206–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dumitru CA, Lang S, Brandau S (2013) Modulation of neutrophil granulocytes in the tumor microenvironment: mechanisms and consequences for tumor progression. Semin Cancer Biol 23(3):141–148

    Article  CAS  PubMed  Google Scholar 

  • Eikenberry S (2009) A tumor cord model for doxorubicin delivery and dose optimization in solid tumors. Theor Biol Med Model 6:16

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Eikenes L, Bruland OS, Brekken C, Davies Cde L (2004) “Collagenase increases the transcapillary pressure gradient and improves the uptake and distribution of monoclonal antibodies in human osteosarcoma xenografts”. Cancer Res 64(14):4768–4773

    Article  CAS  PubMed  Google Scholar 

  • Eikenes L, Tari M, Tufto I, Bruland OS, C. de Lange Davies (2005) Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx) in human osteosarcoma xenografts. Br J Cancer 93(1): 81–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eisinger-Mathason TS, Zhang M, Qiu Q, Skuli N, Nakazawa MS, Karakasheva T, Mucaj V, Shay JE, Stangenberg L, Sadri N, Pure E, Yoon SS, Kirsch DG, Simon MC (2013) Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discov 3(10):1190–1205

    Article  CAS  PubMed  Google Scholar 

  • Enholm B, Paavonen K, Ristimaki A, Kumar V, Gunji Y, Klefstrom J, Kivinen L, Laiho M, Olofsson B, Joukov V, Eriksson U, Alitalo K (1997) Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 14(20):2475–2483

    Article  CAS  PubMed  Google Scholar 

  • Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ (2006) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440(7088):1222–1226

    Article  CAS  PubMed  Google Scholar 

  • Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ (2009) Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15(1):35–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Escorcia FE, Henke E, McDevitt MR, Villa CH, Smith-Jones P, Blasberg RG, Benezra R, Scheinberg DA (2010) Selective killing of tumor neovasculature paradoxically improves chemotherapy delivery to tumors. Cancer Res 70(22):9277–9286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49(6):1374–1403

    Article  CAS  PubMed  Google Scholar 

  • Gangloff A, Hsueh WA, Kesner AL, Kiesewetter DO, Pio BS, Pegram MD, Beryt M, Townsend A, Czernin J, Phelps ME, Silverman DH (2005) Estimation of paclitaxel biodistribution and uptake in human-derived xenografts in vivo with (18)F-fluoropaclitaxel. J Nucl Med 46(11):1866–1871

    CAS  PubMed  Google Scholar 

  • Garcia R, Merino D, Gomez JM, Nistal JF, Hurle MA, Cortajarena AL, Villar AV (2016) Extracellular heat shock protein 90 binding to TGFbeta receptor I participates in TGFbeta-mediated collagen production in myocardial fibroblasts. Cell Signal 28(10):1563–1579

    Article  CAS  PubMed  Google Scholar 

  • Gibson RJ, Bowen JM, Coller JK (2015) What are the predictive factors in the risk and severity of chemotherapy-induced gastrointestinal toxicity?. Future Oncol 11(17):2367–2370

    Article  CAS  PubMed  Google Scholar 

  • Gilkes DM, Chaturvedi P, Bajpai S, Wong CC, Wei H, Pitcairn S, Hubbi ME, Wirtz D, Semenza GL (2013) Collagen prolyl hydroxylases are essential for breast cancer metastasis. Cancer Res 73(11):3285–3296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giordano S, Morosi L, Veglianese P, Licandro SA, Frapolli R, Zucchetti M, Cappelletti G, Falciola L, Pifferi V, Visentin S, D’Incalci M, Davoli E (2016) 3D mass spectrometry imaging reveals a very heterogeneous drug distribution in tumors. Sci Rep 6:37027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glekas AP, Pillarsetty NK, Punzalan B, Khan N, Smith-Jones P, Larson SM (2011) In vivo imaging of Bcr-Abl overexpressing tumors with a radiolabeled imatinib analog as an imaging surrogate for imatinib. J Nucl Med 52(8):1301–1307

    Article  CAS  PubMed  Google Scholar 

  • Gonda K, Shibata M, Sato Y, Washio M, Takeshita H, Shigeta H, Ogura M, Oka S, Sakuramoto S (2017) Elevated neutrophil-to-lymphocyte ratio is associated with nutritional impairment, immune suppression, resistance to S-1 plus cisplatin, and poor prognosis in patients with stage IV gastric cancer. Mol Clin Oncol 7(6):1073–1078

    PubMed  PubMed Central  CAS  Google Scholar 

  • Goodwin RJ, Bunch J, McGinnity DF (2017) Mass spectrometry imaging in oncology drug discovery. Adv Cancer Res 134:133–171

    Article  CAS  PubMed  Google Scholar 

  • Gordon-Weeks AN, Lim SY, Yuzhalin AE, Jones K, Markelc B, Kim KJ, Buzzelli JN, Fokas E, Cao Y, Smart S, Muschel R (2017) Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2-dependent angiogenesis in mice. Hepatology 65(6):1920–1935

    Article  CAS  PubMed  Google Scholar 

  • Goumans MJ, Liu Z, ten Dijke P (2009) TGF-beta signaling in vascular biology and dysfunction. Cell Res 19(1):116–127

    Article  CAS  PubMed  Google Scholar 

  • Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R (2011) Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20(3):300–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gstalder C, Ader I, Cuvillier O (2016) FTY720 (fingolimod) Inhibits HIF1 and HIF2 signaling, promotes vascular remodeling, and chemosensitizes in renal cell carcinoma animal model. Mol Cancer Ther 15(10):2465–2474

    Article  CAS  PubMed  Google Scholar 

  • Gu J, Li Y, Zeng J, Wang B, Ji K, Tang Y, Sun Q (2017) Knockdown of HIF-1alpha by siRNA-expressing plasmid delivered by attenuated Salmonella enhances the antitumor effects of cisplatin on prostate cancer. Sci Rep 7(1):7546

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Guidi AJ, Fischer L, Harris JR, Schnitt SJ (1994) Microvessel density and distribution in ductal carcinoma in situ of the breast. J Natl Cancer Inst 86(8):614–619

    Article  CAS  PubMed  Google Scholar 

  • Guo S, Lin CM, Xu Z, Miao L, Wang Y, Huang L (2014) Co-delivery of cisplatin and rapamycin for enhanced anticancer therapy through synergistic effects and microenvironment modulation. ACS Nano 8(5):4996–5009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Helfrich I, Scheffrahn I, Bartling S, Weis J, von Felbert V, Middleton M, Kato M, Ergun S, Augustin HG, Schadendorf D (2010) Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma. J Exp Med 207(3):491–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalen M, Gerhardt H, Betsholtz C (2007) Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445(7129):776–780

    Article  PubMed  CAS  Google Scholar 

  • Heskamp S, Boerman OC, Molkenboer-Kuenen JD, Oyen WJ, van der Graaf WT, van Laarhoven HW (2013) Bevacizumab reduces tumor targeting of antiepidermal growth factor and anti-insulin-like growth factor 1 receptor antibodies. Int J Cancer 133(2):307–314

    Article  CAS  PubMed  Google Scholar 

  • Hirschi KK, D’Amore PA (1996) Pericytes in the microvasculature. Cardiovasc Res 32(4):687–698

    Article  CAS  PubMed  Google Scholar 

  • Hu Y, Liu J, Huang H (2013) Recent agents targeting HIF-1alpha for cancer therapy. J Cell Biochem 114(3):498–509

    Article  CAS  PubMed  Google Scholar 

  • Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342

    Article  CAS  PubMed  Google Scholar 

  • Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, Hu-Lowe DD, Shalinsky DR, Thurston G, Yancopoulos GD, McDonald DM (2004) Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 165(1):35–52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, Feig C, Nakagawa T, Caldwell ME, Zecchini HI, Lolkema MP, Jiang P, Kultti A, Thompson CB, Maneval DC, Jodrell DI, Frost GI, Shepard HM, Skepper JN, Tuveson DA (2013) Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62(1):112–120

    Article  CAS  PubMed  Google Scholar 

  • Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7(9):987–989

    Article  CAS  PubMed  Google Scholar 

  • Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62

    Article  CAS  PubMed  Google Scholar 

  • Kalluri R (2016) The biology and function of fibroblasts in cancer. Nat Rev Cancer 16(9):582–598

    Article  CAS  PubMed  Google Scholar 

  • Karar J, Maity A (2011) PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci 4:51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kato Y, Okollie B, Artemov D (2006) Noninvasive 1H/13C magnetic resonance spectroscopic imaging of the intratumoral distribution of temozolomide. Magn Reson Med 55(4):755–761

    Article  CAS  PubMed  Google Scholar 

  • Kattel K, Mondal G, Lin F, Kumar V, Mahato RI (2017) Biodistribution of self-assembling polymer-gemcitabine conjugate after systemic administration into orthotopic pancreatic tumor bearing mice. Mol Pharm 14(5):1365–1372

    Article  CAS  PubMed  Google Scholar 

  • Kesner AL, Hsueh WA, Htet NL, Pio BS, Czernin J, Pegram MD, Phelps ME, Silverman DH (2007) Biodistribution and predictive value of 18F-fluorocyclophosphamide in mice bearing human breast cancer xenografts. J Nucl Med 48(12):2021–2027

    Article  CAS  PubMed  Google Scholar 

  • Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SA, Fack F, Thorsen F, Taxt T, Bartos M, Jirik R, Miletic H, Wang J, Stieber D, Stuhr L, Moen I, Rygh CB, Bjerkvig R, Niclou SP (2011) Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci USA 108(9):3749–3754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khan S, Ebeling MC, Chauhan N, Thompson PA, Gara RK, Ganju A, Yallapu MM, Behrman SW, Zhao H, Zafar N, Singh MM, Jaggi M, Chauhan SC (2015) Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer. Cancer Res 75(11):2292–2304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klee NS, McCarthy CG, Martinez-Quinones P, Webb RC (2017) Out of the frying pan and into the fire: damage-associated molecular patterns and cardiovascular toxicity following cancer therapy. Ther Adv Cardiovasc Dis 11(11):297–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kolenda J, Jensen SS, Aaberg-Jessen C, Christensen K, Andersen C, Brunner N, Kristensen BW (2011) Effects of hypoxia on expression of a panel of stem cell and chemoresistance markers in glioblastoma-derived spheroids. J Neurooncol 103(1):43–58

    Article  CAS  PubMed  Google Scholar 

  • Konerding MA, Fait E, Gaumann A (2001) 3D microvascular architecture of pre-cancerous lesions and invasive carcinomas of the colon. Br J Cancer 84(10):1354–1362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kozono S, Ohuchida K, Eguchi D, Ikenaga N, Fujiwara K, Cui L, Mizumoto K, Tanaka M (2013) Pirfenidone inhibits pancreatic cancer desmoplasia by regulating stellate cells. Cancer Res 73(7):2345–2356

    Article  CAS  PubMed  Google Scholar 

  • Krysan K, Cui X, Gardner BK, Reckamp KL, Wang X, Hong L, Walser TC, Rodriguez NL, Pagano PC, Garon EB, Brothers JF II, Elashoff D, Lee JM, Spira AE, Sharma S, Fishbein MC, Dubinett SM (2013) Elevated neutrophil gelatinase-associated lipocalin contributes to erlotinib resistance in non-small cell lung cancer. Am J Transl Res 5(5):481–496

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kunkel P, Ulbricht U, Bohlen P, Brockmann MA, Fillbrandt R, Stavrou D, Westphal M, Lamszus K (2001) Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2. Cancer Res 61(18):6624–6628

    CAS  PubMed  Google Scholar 

  • Kurdziel KA, Kalen JD, Hirsch JI, Wilson JD, Bear HD, Logan J, McCumisky J, Moorman-Sykes K, Adler S, Choyke PL (2011) Human dosimetry and preliminary tumor distribution of 18F-fluoropaclitaxel in healthy volunteers and newly diagnosed breast cancer patients using PET/CT. J Nucl Med 52(9):1339–1345

    Article  CAS  PubMed  Google Scholar 

  • Laginha KM, Verwoert S, Charrois GJ, Allen TM (2005) Determination of doxorubicin levels in whole tumor and tumor nuclei in murine breast cancer tumors. Clin Cancer Res 11(19 Pt 1):6944–6949

    Article  CAS  PubMed  Google Scholar 

  • Lalami Y, Specenier PM, Awada A, Lacombe D, Liberatoscioli C, Fortpied C, El-Hariry I, Bogaerts J, Andry G, Langendijk JA, Vermorken JB (2012) EORTC 24051: unexpected side effects in a phase I study of TPF induction chemotherapy followed by chemoradiation with lapatinib, a dual EGFR/ErbB2 inhibitor, in patients with locally advanced resectable larynx and hypopharynx squamous cell carcinoma. Radiother Oncol 105(2):238–240

    Article  CAS  PubMed  Google Scholar 

  • Lamichhane N, Dewkar GK, Sundaresan G, Wang L, Jose P, Otabashi M, Morelle JL, Farrell N, Zweit J (2017) (18)F-labeled carboplatin derivative for PET imaging of platinum drug distribution. J Nucl Med 58(12):1997–2003

    Article  CAS  PubMed  Google Scholar 

  • Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56(20):4625–4629

    CAS  PubMed  Google Scholar 

  • Liang WC, Wu X, Peale FV, Lee CV, Meng YG, Gutierrez J, Fu L, Malik AK, Gerber HP, Ferrara N, Fuh G (2006) Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF. J Biol Chem 281(2):951–961

    Article  CAS  PubMed  Google Scholar 

  • Liao F, Doody JF, Overholser J, Finnerty B, Bassi R, Wu Y, Dejana E, Kussie P, Bohlen P, Hicklin DJ (2002) Selective targeting of angiogenic tumor vasculature by vascular endothelial-cadherin antibody inhibits tumor growth without affecting vascular permeability. Cancer Res 62(9):2567–2575

    CAS  PubMed  Google Scholar 

  • Liu XQ, Xiong MH, Shu XT, Tang RZ, Wang J (2012a) Therapeutic delivery of siRNA silencing HIF-1 alpha with micellar nanoparticles inhibits hypoxic tumor growth. Mol Pharm 9(10):2863–2874

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Liao S, Diop-Frimpong B, Chen W, Goel S, Naxerova K, Ancukiewicz M, Boucher Y, Jain RK, Xu L (2012b) TGF-beta blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc Natl Acad Sci USA 109(41):16618–16623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mammoto T, Jiang A, Jiang E, Panigrahy D, Kieran MW, Mammoto A (2013) Role of collagen matrix in tumor angiogenesis and glioblastoma multiforme progression. Am J Pathol 183(4):1293–1305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsumoto S, Batra S, Saito K, Yasui H, Choudhuri R, Gadisetti C, Subramanian S, Devasahayam N, Munasinghe JP, Mitchell JB, Krishna MC (2011) Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia. Cancer Res 71(20):6350–6359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McDonald LT, Russell DL, Kelly RR, Xiong Y, Motamarry A, Patel RK, Jones JA, Watson PM, Turner DP, Watson DK, Soloff AC, Findlay VJ, LaRue AC (2015) Hematopoietic stem cell-derived cancer-associated fibroblasts are novel contributors to the pro-tumorigenic microenvironment. Neoplasia 17(5):434–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM (2017) Anthracycline chemotherapy cardiotoxicity. Cardiovasc Drugs Ther 31(1):63–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Memon AA, Jakobsen S, Dagnaes-Hansen F, Sorensen BS, Keiding S, Nexo E (2009) Positron emission tomography (PET) imaging with [11C]-labeled erlotinib: a micro-PET study on mice with lung tumor xenografts. Cancer Res 69(3):873–878

    Article  CAS  PubMed  Google Scholar 

  • Merouani A, Davidson SA, Schrier RW (1997) Increased nephrotoxicity of combination taxol and cisplatin chemotherapy in gynecologic cancers as compared to cisplatin alone. Am J Nephrol 17(1):53–58

    Article  CAS  PubMed  Google Scholar 

  • Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357(26):2666–2676

    Article  CAS  PubMed  Google Scholar 

  • Minow RA, Stern MH, Casey JH, Rodriguez V, Luna MA (1976) Clinico-pathologic correlation of liver damage in patients treated with 6-mercaptopurine and adriamycin. Cancer 38(4):1524–1528

    Article  CAS  PubMed  Google Scholar 

  • Minowa T, Kawano K, Kuribayashi H, Shiraishi K, Sugino T, Hattori Y, Yokoyama M, Maitani Y (2009) Increase in tumour permeability following TGF-beta type I receptor-inhibitor treatment observed by dynamic contrast-enhanced MRI. Br J Cancer 101(11):1884–1890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, Hewitt S, Udupi GM, Gallagher WM, Wegner C, West BL, Wang-Gillam A, Goedegebuure P, Linehan DC, DeNardo DG (2013) Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 73(3):1128–1141

    Article  CAS  PubMed  Google Scholar 

  • Miyazaki S, Kikuchi H, Iino I, Uehara T, Setoguchi T, Fujita T, Hiramatsu Y, Ohta M, Kamiya K, Kitagawa K, Kitagawa M, Baba S, Konno H (2014) Anti-VEGF antibody therapy induces tumor hypoxia and stanniocalcin 2 expression and potentiates growth of human colon cancer xenografts. Int J Cancer 135(2):295–307

    Article  CAS  PubMed  Google Scholar 

  • Monteiro LOF, Fernandes RS, Castro LC, Cardoso VN, Oliveira MC, Townsend DM, Ferretti A, Rubello D, Leite EA, de Barros ALB (2017) Technetium-99m radiolabeled paclitaxel as an imaging probe for breast cancer in vivo. Biomed Pharmacother 89:146–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morosi L, Spinelli P, Zucchetti M, Pretto F, Carra A, D’Incalci M, Giavazzi R, Davoli E (2013a) Determination of paclitaxel distribution in solid tumors by nano-particle assisted laser desorption ionization mass spectrometry imaging. PLoS One 8(8):e72532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morosi L, Zucchetti M, D’Incalci M, Davoli E (2013b) Imaging mass spectrometry: challenges in visualization of drug distribution in solid tumors. Curr Opin Pharmacol 13(5):807–812

    Article  CAS  PubMed  Google Scholar 

  • Murphy PM (1997) Neutrophil receptors for interleukin-8 and related CXC chemokines. Semin Hematol 34(4):311–318

    CAS  PubMed  Google Scholar 

  • Neugut AI, Prigerson HG (2017) Curative, life-extending, and palliative chemotherapy: new outcomes need new names. Oncologist 22(8):883–885

    Article  PubMed  PubMed Central  Google Scholar 

  • Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, Lin HC, Yancopoulos GD, Thurston G (2006) Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444(7122):1032–1037

    Article  CAS  PubMed  Google Scholar 

  • Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA 103(33):12493–12498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Malley DM, Richardson DL, Rheaume PS, Salani R, Eisenhauer EL, McCann GA, Fowler JM, Copeland LJ, Cohn DE, Backes FJ (2011) Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer. Gynecol Oncol 121(2):269–272

    Article  PubMed  CAS  Google Scholar 

  • Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, Corbo V, Oni TE, Hearn SA, Lee EJ, Chio II, Hwang CI, Tiriac H, Baker LA, Engle DD, Feig C, Kultti A, Egeblad M, Fearon DT, Crawford JM, Clevers H, Park Y, Tuveson DA (2017) Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med 214(3):579–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, De Jesus-Acosta A, Sharma P, Heidari P, Mahmood U, Chin L, Moses HL, Weaver VM, Maitra A, Allison JP, LeBleu VS, Kalluri R (2014) Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25(6):719–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pankova D, Chen Y, Terajima M, Schliekelman MJ, Baird BN, Fahrenholtz M, Sun L, Gill BJ, Vadakkan TJ, Kim MP, Ahn YH, Roybal JD, Liu X, Parra Cuentas ER, Rodriguez J, Wistuba II, Creighton CJ, Gibbons DL, Hicks JM, Dickinson ME, West JL, Grande-Allen KJ, Hanash SM, Yamauchi M, Kurie JM (2016) Cancer-associated fibroblasts induce a collagen cross-link switch in tumor stroma. Mol Cancer Res 14(3):287–295

    Article  CAS  PubMed  Google Scholar 

  • Pasanen I, Lehtonen S, Sormunen R, Skarp S, Lehtilahti E, Pietila M, Sequeiros RB, Lehenkari P, Kuvaja P (2016) Breast cancer carcinoma-associated fibroblasts differ from breast fibroblasts in immunological and extracellular matrix regulating pathways. Exp Cell Res 344(1):53–66

    Article  CAS  PubMed  Google Scholar 

  • Penack O, Henke E, Suh D, King CG, Smith OM, Na IK, Holland AM, Ghosh A, Lu SX, Jenq RR, Liu C, Murphy GF, Lu TT, May C, Scheinberg DA, Gao DC, Mittal V, Heller G, Benezra R, van den Brink MR (2010) Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth. J Natl Cancer Inst 102(12):894–908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perez EA (1998) Paclitaxel and cardiotoxicity. J Clin Oncol 16(11):3481–3482

    Article  CAS  PubMed  Google Scholar 

  • Peyrol S, Raccurt M, Gerard F, Gleyzal C, Grimaud JA, Sommer P (1997) Lysyl oxidase gene expression in the stromal reaction to in situ and invasive ductal breast carcinoma. Am J Pathol 150(2):497–507

    CAS  PubMed  PubMed Central  Google Scholar 

  • Phung TL, Ziv K, Dabydeen D, Eyiah-Mensah G, Riveros M, Perruzzi C, Sun J, Monahan-Earley RA, Shiojima I, Nagy JA, Lin MI, Walsh K, Dvorak AM, Briscoe DM, Neeman M, Sessa WC, Dvorak HF, Benjamin LE (2006) Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 10(2):159–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Porsch H, Bernert B, Mehic M, Theocharis AD, Heldin CH, Heldin P (2013) Efficient TGFbeta-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2. Oncogene 32(37):4355–4365

    Article  CAS  PubMed  Google Scholar 

  • Prewett M, Huber J, Li Y, Santiago A, O’Connor W, King K, Overholser J, Hooper A, Pytowski B, Witte L, Bohlen P, Hicklin DJ (1999) Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res 59(20):5209–5218

    CAS  PubMed  Google Scholar 

  • Primeau AJ, Rendon A, Hedley D, Lilge L, Tannock IF (2005) The distribution of the anticancer drug Doxorubicin in relation to blood vessels in solid tumors. Clin Cancer Res 11(24 Pt 1):8782–8788

    Article  CAS  PubMed  Google Scholar 

  • Provenzano PP, Hingorani SR (2013) Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br J Cancer 108(1):1–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, White JG, Keely PJ (2008) Collagen density promotes mammary tumor initiation and progression. BMC Med 6:11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21(3):418–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K, Gillespie S, Rodman C, Luo CL, Mroz EA, Emerick KS, Deschler DG, Varvares MA, Mylvaganam R, Rozenblatt-Rosen O, Rocco JW, Faquin WC, Lin DT, Regev A, Bernstein BE (2017) Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell 171(7):1611–1624 e1624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qayum N, Im J, Stratford MR, Bernhard EJ, McKenna WG, Muschel RJ (2012) Modulation of the tumor microvasculature by phosphoinositide-3 kinase inhibition increases doxorubicin delivery in vivo. Clin Cancer Res 18(1):161–169

    Article  CAS  PubMed  Google Scholar 

  • Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression metastasis. Cell 141(1):39–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qiao Y, Zhang C, Li A, Wang D, Luo Z, Ping Y, Zhou B, Liu S, Li H, Yue D, Zhang Z, Chen X, Shen Z, Lian J, Li Y, Wang S, Li F, Huang L, Wang L, Zhang B, Yu J, Qin Z, Zhang Y (2018) IL6 derived from cancer-associated fibroblasts promotes chemoresistance via CXCR7 in esophageal squamous cell carcinoma. Oncogene 37(7):873–883

    Article  CAS  PubMed  Google Scholar 

  • Rohrig F, Vorlova S, Hoffmann H, Wartenberg M, Escorcia FE, Keller S, Tenspolde M, Weigand I, Gatzner S, Manova K, Penack O, Scheinberg DA, Rosenwald A, Ergun S, Granot Z, Henke E (2017) VEGF-ablation therapy reduces drug delivery and therapeutic response in ECM-dense tumors. Oncogene 36(1):1–12

    Article  CAS  PubMed  Google Scholar 

  • Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, Akerud P, De Mol M, Salomaki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, Van Ginderachter JA, De Palma M, Dewerchin M, Claesson-Welsh L, Carmeliet P (2011) HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19(1):31–44

    Article  CAS  PubMed  Google Scholar 

  • Rossow L, Veitl S, Vorlova S, Wax JK, Kuhn AE, Maltzahn V, Upcin B, Karl F, Hoffmann H, Gatzner S, Kallius M, Nandigama R, Scheld D, Irmak S, Herterich S, Zernecke A, Ergun S, Henke E (2018) LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy. Oncogene 37(36):4921–4940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruan GX, Kazlauskas A (2012) Axl is essential for VEGF-A-dependent activation of PI3K/Akt. EMBO J 31(7):1692–1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rubin MA, Buyyounouski M, Bagiella E, Sharir S, Neugut A, Benson M, de la Taille A, Katz AE, Olsson CA, Ennis RD (1999) Microvessel density in prostate cancer: lack of correlation with tumor grade, pathologic stage, and clinical outcome. Urology 53(3):542–547

    Article  CAS  PubMed  Google Scholar 

  • Rubin K, Sjoquist M, Gustafsson AM, Isaksson B, Salvessen G, Reed RK (2000) Lowering of tumoral interstitial fluid pressure by prostaglandin E(1) is paralleled by an increased uptake of (51)Cr-EDTA. Int J Cancer 86(5):636–643

    Article  CAS  PubMed  Google Scholar 

  • Sagiv JY, Michaeli J, Assi S, Mishalian I, Kisos H, Levy L, Damti P, Lumbroso D, Polyansky L, Sionov RV, Ariel A, Hovav AH, Henke E, Fridlender ZG, Granot Z (2015) Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep 10(4):562–573

    Article  CAS  PubMed  Google Scholar 

  • Saleem A, Searle GE, Kenny LM, Huiban M, Kozlowski K, Waldman AD, Woodley L, Palmieri C, Lowdell C, Kaneko T, Murphy PS, Lau MR, Aboagye EO, Coombes RC (2015) Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer. EJNMMI Res 5:30

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355(24):2542–2550

    Article  CAS  PubMed  Google Scholar 

  • Scapini P, Calzetti F, Cassatella MA (1999) On the detection of neutrophil-derived vascular endothelial growth factor (VEGF). J Immunol Methods 232(1–2):121–129

    Article  CAS  PubMed  Google Scholar 

  • Schaider H, Oka M, Bogenrieder T, Nesbit M, Satyamoorthy K, Berking C, Matsushima K, Herlyn M (2003) Differential response of primary and metastatic melanomas to neutrophils attracted by IL-8. Int J Cancer 103(3):335–343

    Article  CAS  PubMed  Google Scholar 

  • Schober M, Jesenofsky R, Faissner R, Weidenauer C, Hagmann W, Michl P, Heuchel RL, Haas SL, Lohr JM (2014) Desmoplasia and chemoresistance in pancreatic cancer. Cancers (Basel) 6(4):2137–2154

    Article  CAS  Google Scholar 

  • Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, Goodwin LM, Smethurst E, Mason S, Blyth K, McGarry L, James D, Shanks E, Kalna G, Saunders RE, Jiang M, Howell M, Lassailly F, Thin MZ, Spencer-Dene B, Stamp G, van den Broek NJ, Mackay G, Bulusu V, Kamphorst JJ, Tardito S, Strachan D, Harris AL, Aboagye EO, Critchlow SE, Wakelam MJ, Schulze A, Gottlieb E (2015) Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27(1):57–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schutze F, Rohrig F, Vorlova S, Gatzner S, Kuhn A, Ergun S, Henke E (2015) Inhibition of lysyl oxidases improves drug diffusion and increases efficacy of cytotoxic treatment in 3D tumor models. Sci Rep 5:17576

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, Bhagwandin V, Tabruyn SP, You WK, Chapman HA, Christensen JG, Aftab DT, McDonald DM (2012) Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2(3):270–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shani J, Bertram J, Russell C, Dahalan R, Chen DC, Parti R, Ahmadi J, Kempf RA, Kawada TK, Muggia FM et al (1989) Noninvasive monitoring of drug biodistribution and metabolism: studies with intraarterial Pt-195m-cisplatin in humans. Cancer Res 49(7):1877–1881

    CAS  PubMed  Google Scholar 

  • Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, Collisson EA, Connor F, Van Dyke T, Kozlov S, Martin P, Tseng TW, Dawson DW, Donahue TR, Masamune A, Shimosegawa T, Apte MV, Wilson JS, Ng B, Lau SL, Gunton JE, Wahl GM, Hunter T, Drebin JA, O’Dwyer PJ, Liddle C, Tuveson DA, Downes M, Evans RM (2014) Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159(1):80–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42(6):717–727

    Article  CAS  PubMed  Google Scholar 

  • Singh Jaggi J, Henke E, Seshan SV, Kappel BJ, Chattopadhyay D, May C, McDevitt MR, Nolan D, Mittal V, Benezra R, Scheinberg DA (2007) Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization. PLoS One 2(3):e267

    Article  PubMed  CAS  Google Scholar 

  • Sionov RV, Fridlender ZG, Granot Z (2015) The multifaceted roles neutrophils play in the tumor microenvironment. Cancer Microenviron 8(3):125–158

    Article  CAS  PubMed  Google Scholar 

  • Stockmann C, Doedens A, Weidemann A, Zhang N, Takeda N, Greenberg JI, Cheresh DA, Johnson RS (2008) Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456(7223):814–818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su S, Chen J, Yao H, Liu J, Yu S, Lao L, Wang M, Luo M, Xing Y, Chen F, Huang D, Zhao J, Yang L, Liao D, Su F, Li M, Liu Q, Song E (2018) CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 172(4):841–856 e816

    Article  CAS  PubMed  Google Scholar 

  • Sullivan R, Pare GC, Frederiksen LJ, Semenza GL, Graham CH (2008) Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Mol Cancer Ther 7(7):1961–1973

    Article  CAS  PubMed  Google Scholar 

  • Sunderkotter C, Goebeler M, Schulze-Osthoff K, Bhardwaj R, Sorg C (1991) Macrophage-derived angiogenesis factors. Pharmacol Ther 51(2):195–216

    Article  CAS  PubMed  Google Scholar 

  • Taillibert S, Le Rhun E, Chamberlain MC (2016) Chemotherapy-related neurotoxicity. Curr Neurol Neurosci Rep 16(9):81

    Article  PubMed  CAS  Google Scholar 

  • Tang N, Wang L, Esko J, Giordano FJ, Huang Y, Gerber HP, Ferrara N, Johnson RS (2004) Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6(5):485–495

    Article  CAS  PubMed  Google Scholar 

  • Tang YA, Chen YF, Bao Y, Mahara S, Yatim S, Oguz G, Lee PL, Feng M, Cai Y, Tan EY, Fong SS, Yang ZH, Lan P, Wu XJ, Yu Q (2018) Hypoxic tumor microenvironment activates GLI2 via HIF-1alpha and TGF-beta2 to promote chemoresistance in colorectal cancer. Proc Natl Acad Sci USA 115(26):E5990–E5999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tian Hu S, Brandle E, Zbinden G (1983) Inhibition of cardiotoxic, nephrotoxic and neurotoxic effects of doxorubicin by ICRF-159. Pharmacology 26(4):210–220

    Article  CAS  PubMed  Google Scholar 

  • Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64(11):3731–3736

    Article  CAS  PubMed  Google Scholar 

  • Torok S, Rezeli M, Kelemen O, Vegvari A, Watanabe K, Sugihara Y, Tisza A, Marton T, Kovacs I, Tovari J, Laszlo V, Helbich TH, Hegedus B, Klikovits T, Hoda MA, Klepetko W, Paku S, Marko-Varga G, Dome B (2017) Limited tumor tissue drug penetration contributes to primary resistance against angiogenesis inhibitors. Theranostics 7(2):400–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsubata Y, Hayashi M, Tanino R, Aikawa H, Ohuchi M, Tamura K, Fujiwara Y, Isobe T, Hamada A (2017) Evaluation of the heterogeneous tissue distribution of erlotinib in lung cancer using matrix-assisted laser desorption ionization mass spectrometry imaging. Sci Rep 7(1):12622

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tsutsui S, Yasuda K, Suzuki K, Tahara K, Higashi H, Era S (2005) Macrophage infiltration and its prognostic implications in breast cancer: the relationship with VEGF expression and microvessel density. Oncol Rep 14(2):425–431

    CAS  PubMed  Google Scholar 

  • van Vlerken LE, Duan Z, Little SR, Seiden MV, Amiji MM (2008) Biodistribution and pharmacokinetic analysis of Paclitaxel and ceramide administered in multifunctional polymer-blend nanoparticles in drug resistant breast cancer model. Mol Pharm 5(4):516–526

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • van Meeteren LA, Goumans MJ, ten Dijke P (2011) TGF-beta receptor signaling pathways in angiogenesis; emerging targets for anti-angiogenesis therapy. Curr Pharm Biotechnol 12(12):2108–2120

    Article  PubMed  Google Scholar 

  • van der Veldt AA, Lammertsma AA (2014) In vivo imaging as a pharmacodynamic marker. Clin Cancer Res 20(10):2569–2577

    Article  PubMed  CAS  Google Scholar 

  • van der Veldt AA, Hendrikse NH, Smit EF, Mooijer MP, Rijnders AY, Gerritsen WR, van der Hoeven JJ, Windhorst AD, Lammertsma AA, Lubberink M (2010) Biodistribution and radiation dosimetry of 11C-labelled docetaxel in cancer patients. Eur J Nucl Med Mol Imaging 37(10):1950–1958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van der Veldt AA, Lubberink M, Greuter HN, Comans EF, Herder GJ, Yaqub M, Schuit RC, van Lingen A, Rizvi SN, Mooijer MP, Rijnders AY, Windhorst AD, Smit EF, Hendrikse NH, Lammertsma AA (2011) Absolute quantification of [(11)C]docetaxel kinetics in lung cancer patients using positron emission tomography. Clin Cancer Res 17(14):4814–4824

    Article  PubMed  CAS  Google Scholar 

  • Van der Veldt AA, Lubberink M, Bahce I, Walraven M, de Boer MP, Greuter HN, Hendrikse NH, Eriksson J, Windhorst AD, Postmus PE, Verheul HM, Serne EH, Lammertsma AA, Smit EF (2012) Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell 21(1):82–91

    Article  PubMed  CAS  Google Scholar 

  • Viola A, Sarukhan A, Bronte V, Molon B (2012) The pros and cons of chemokines in tumor immunology. Trends Immunol 33(10):496–504

    Article  CAS  PubMed  Google Scholar 

  • Voloshenyuk TG, Landesman ES, Khoutorova E, Hart AD, Gardner JD (2011) Induction of cardiac fibroblast lysyl oxidase by TGF-beta1 requires PI3K/Akt, Smad3, and MAPK signaling. Cytokine 55(1):90–97

    Article  CAS  PubMed  Google Scholar 

  • Walshe TE, Saint-Geniez M, Maharaj AS, Sekiyama E, Maldonado AE, D’Amore PA (2009) TGF-beta is required for vascular barrier function, endothelial survival and homeostasis of the adult microvasculature. PLoS One 4(4):e5149

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Weisshardt P, Trarbach T, Durig J, Paul A, Reis H, Tilki D, Miroschnik I, Ergun S, Klein D (2012) Tumor vessel stabilization and remodeling by anti-angiogenic therapy with bevacizumab. Histochem Cell Biol 137(3):391–401

    Article  CAS  PubMed  Google Scholar 

  • Whatcott CJ, Ng S, Barrett MT, Hostetter G, Von Hoff DD, Han H (2017) Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer. PLoS One 12(8):e0183871

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10(2):145–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn LL, Jain RK (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6(6):553–563

    CAS  PubMed  Google Scholar 

  • Xiao K, Li Y, Lee JS, Gonik AM, Dong T, Fung G, Sanchez E, Xing L, Cheng HR, Luo J, Lam KS (2012) “OA02” peptide facilitates the precise targeting of paclitaxel-loaded micellar nanoparticles to ovarian cancer in vivo. Cancer Res 72(8):2100–2110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie J, Wang C, Huang DY, Zhang Y, Xu J, Kolesnikov SS, Sung KL, Zhao H (2013) TGF-beta1 induces the different expressions of lysyl oxidases and matrix metalloproteinases in anterior cruciate ligament and medial collateral ligament fibroblasts after mechanical injury. J Biomech 46(5):890–898

    Article  PubMed  Google Scholar 

  • Xiong G, Deng L, Zhu J, Rychahou PG, Xu R (2014) Prolyl-4-hydroxylase alpha subunit 2 promotes breast cancer progression and metastasis by regulating collagen deposition. BMC Cancer 14:1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xu S, Yang Z, Jin P, Yang X, Li X, Wei X, Wang Y, Long S, Zhang T, Chen G, Sun C, Ma D, Gao Q (2018) Metformin suppresses tumor progression by inactivating stromal fibroblasts in ovarian cancer. Mol Cancer Ther 17(6):1291–1302

    Article  CAS  PubMed  Google Scholar 

  • Yan T, Deng S, Metzger A, Godtel-Armbrust U, Porter AC, Wojnowski L (2009) Topoisomerase II{alpha}-dependent and -independent apoptotic effects of dexrazoxane and doxorubicin. Mol Cancer Ther 8(5):1075–1085

    Article  CAS  PubMed  Google Scholar 

  • Yu H, Tang Z, Zhang D, Song W, Zhang Y, Yang Y, Ahmad Z, Chen X (2015) Pharmacokinetics, biodistribution and in vivo efficacy of cisplatin loaded poly(l-glutamic acid)-g-methoxy poly(ethylene glycol) complex nanoparticles for tumor therapy. J Control Release 205:89–97

    Article  CAS  PubMed  Google Scholar 

  • Zaffryar-Eilot S, Marshall D, Voloshin T, Bar-Zion A, Spangler R, Kessler O, Ghermazien H, Brekhman V, Suss-Toby E, Adam D, Shaked Y, Smith V, Neufeld G (2013) Lysyl oxidase-like-2 promotes tumour angiogenesis and is a potential therapeutic target in angiogenic tumours. Carcinogenesis 34(10):2370–2379

    Article  CAS  PubMed  Google Scholar 

  • Zagzag D, Zhong H, Scalzitti JM, Laughner E, Simons JW, Semenza GL (2000) Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer 88(11):2606–2618

    Article  CAS  PubMed  Google Scholar 

  • Zhang Q, Bindokas V, Shen J, Fan H, Hoffman RM, Xing HR (2011) Time-course imaging of therapeutic functional tumor vascular normalization by antiangiogenic agents. Mol Cancer Ther 10(7):1173–1184

    Article  CAS  PubMed  Google Scholar 

  • Zhao Q, Eichten A, Parveen A, Adler C, Huang Y, Wang W, Ding Y, Adler A, Nevins T, Ni M, Wei Y, Thurston G (2018) Single-cell transcriptome analyses reveal endothelial cell heterogeneity in tumors and changes following antiangiogenic treatment. Cancer Res 78(9):2370–2382

    Article  CAS  PubMed  Google Scholar 

  • Zode GS, Clark AF, Wordinger RJ (2009) Bone morphogenetic protein 4 inhibits TGF-beta2 stimulation of extracellular matrix proteins in optic nerve head cells: role of gremlin in ECM modulation. Glia 57(7):755–766

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Anatomy and Cell Biology, Universität Würzburg, Koellikerstrasse 6, 97070, Würzburg, Germany

    Rajender Nandigama, Berin Upcin, Süleyman Ergün & Erik Henke

  2. Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Bertal H. Aktas

Authors
  1. Rajender Nandigama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Berin Upcin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bertal H. Aktas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Süleyman Ergün
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Erik Henke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Erik Henke.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nandigama, R., Upcin, B., Aktas, B.H. et al. Restriction of drug transport by the tumor environment. Histochem Cell Biol 150, 631–648 (2018). https://doi.org/10.1007/s00418-018-1744-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-018-1744-z

Keywords

Search

Navigation