Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment

Advanced Drug Delivery Reviews

Volumn 99, Issue , 2016, Pages 186-196

  Ishii, Genichiro ^a   Ochiai, Atsushi ^a   Neri, Shinya ^a  

^a NATIONAL CANCER CENTER HOSPITAL EAST   (Japan)

Author keywords

Cancer associated fibroblast; Extracellular matrix; Heterogeneity; Microenvironment; Stromal cells; Therapeutic sensitivity; Tumor progression

Indexed keywords

CELL CULTURE; CYTOLOGY; DISEASES; ENZYME ACTIVITY; FIBROBLASTS; TUMORS;

EXTRACELLULAR MATRICES; HETEROGENEITY; MICROENVIRONMENTS; STROMAL CELLS; THERAPEUTIC SENSITIVITY; TUMOR PROGRESSIONS;

CELLS;

CHIR 265; CONNECTIVE TISSUE GROWTH FACTOR; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; EVEROLIMUS; FIBRONECTIN; FLUOROURACIL; GEMCITABINE; INTERLEUKIN 11; MITOGEN ACTIVATED PROTEIN KINASE; NAVITOCLAX; OXALIPLATIN; PATIDEGIB; PHOSPHATIDYLINOSITOL 3 KINASE; PODOPLANIN; SCATTER FACTOR; SOMATOMEDIN; SONIC HEDGEHOG PROTEIN; STROMAL CELL DERIVED FACTOR 1; TAMOXIFEN; TRANSFORMING GROWTH FACTOR BETA; VASCULOTROPIN; VITAMIN D RECEPTOR; COLLAGEN;

BILE DUCT CARCINOMA; BREAST CANCER; BREAST CARCINOMA; CANCER ASSOCIATED FIBROBLAST; CANCER GENETICS; CANCER GROWTH; CANCER STEM CELL; CARCINOGENESIS; CELL COMMUNICATION; CELL POPULATION; CELL PROLIFERATION; CELL SURVIVAL; CELL VIABILITY; COLON CANCER; COLON CARCINOMA; CYTOTOXICITY; ENDOTHELIUM CELL; EPITHELIAL MESENCHYMAL TRANSITION; EXTRACELLULAR MATRIX; FIBROBLAST; GENETIC HETEROGENEITY; HUMAN; IMMUNE RESPONSE; IMMUNOGENICITY; IMMUNOMODULATION; IMMUNOREGULATION; MORPHOLOGY; NONHUMAN; PANCREAS ADENOCARCINOMA; PHENOTYPE; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; REGULATORY T LYMPHOCYTE; REVIEW; STROMA CELL; TUMOR MICROENVIRONMENT; ANIMAL; DISEASE COURSE; METABOLISM; PATHOLOGY; PHYSIOLOGY;

ANIMALS; CANCER-ASSOCIATED FIBROBLASTS; COLLAGEN; DISEASE PROGRESSION; HUMANS; STROMAL CELLS; TUMOR MICROENVIRONMENT;

EID: 84940121469     PISSN: 0169409X     EISSN: 18728294     Source Type: Journal    
DOI: 10.1016/j.addr.2015.07.007     Document Type: Review

References (71)

1. Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889, 1571-1573.
2. Bhowmick N., Chytiil A., Plieth D., Gorska A., Dumont N., Shappel S., Washington M., Neilson E., Moses H. TGF-β signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004, 303:847-851.
3. Ronnov-Jessen L., Petersen O.W., Koteliansky V.E., Bissell M.J. The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J. Clin. Invest. 1995, 95:859-873.
4. Orimo A., Weinberg R.A. Heterogeneity of stromal fibroblasts in tumors. Cancer Biol. Ther. 2007, 6:618-619.
5. Ishii G., Sangai T., Oda T., Aoyagi Y., Hasebe T., Kanomata N., Endoh Y., Okumura C., Okuhara Y., Magae J., Emura M., Ochiya T., Ochiai A. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem. Biophys. Res. Commun. 2003, 309:232-240.
6. Ishii G., Ito T.K., Aoyagi K., Fujimoto H., Chiba H., Hasebe T., Fujii S., Nagai K., Sasaki H., Ochiai A. Presence of human circulating progenitor cells for cancer stromal fibroblasts in the blood of lung cancer patients. Stem Cells 2007, 25:1469-1477.
7. Sugimoto H., Mundel T.M., Kieran M.W., Kalluri R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol. Ther. 2006, 5:1640-1646.
8. Polanska U.M., Orimo A. Carcinoma-associated fibroblasts: non-neoplastic tumour-promoting mesenchymal cells. J. Cell. Physiol. 2013, 228:1651-1657.
9. Augsten M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front. Oncol. 2014, 4:62.
10. Kawase A., Ishii G., Nagai K., Ito T., Nagano T., Murata Y., Hishida T., Nishimura M., Yoshida J., Suzuki K., Ochiai A. Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. Int. J. Cancer 2008, 123:1053-1059.
11. Ono S., Ishii G., Nagai K., Takuwa T., Yoshida J., Nishimura M., Hishida T., Aokage K., Fujii S., Ikeda N., Ochiai A. Podoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: usefulness of combining analysis of both cancer cell phenotype and cancer-associated fibroblast phenotype. Chest 2013, 143:963-970.
12. Pula B., Jethon A., Piotrowska A., Gomulkiewicz A., Owczarek T., Calik J., Wojnar A., Witkiewicz W., Rys J., Ugorski M., Dziegiel P., Podhorska-Okolow M. Podoplanin expression by cancer-associated fibroblasts predicts poor outcome in invasive ductal breast carcinoma. Histopathology 2011, 59:1249-1260.
13. Hoshino A., Ishii G., Ito T., Aoyagi K., Ohtaki Y., Nagai K., Sasaki H., Ochiai A. Podoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation: podoplanin in fibroblast functions for tumor progression. Cancer Res. 2011, 71:4769-4779.
14. Wikberg M.L., Edin S., Lundberg I.V., Van Guelpen B., Dahlin A.M., Rutegård J., Stenling R., Oberg A., Palmqvist R. High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis. Tumour Biol. 2013, 34:1013-1020.
15. Zhao H., Peehl D.M. Tumor-promoting phenotype of CD90hi prostate cancer-associated fibroblasts. Prostate 2009, 69:991-1000.
16. Chaffer C.L., Weinberg R.A. A perspective on cancer cell metastasis. Science 2011, 331:1559-1564.
17. Chen W.J., Ho C.C., Chang Y.L., Chen H.Y., Lin C.A., Ling T.Y., Yu S.L., Yuan S.S., Chen Y.J., Lin C.Y., Pan S.H., Chou H.Y., Chen Y.J., Chang G.C., Chu W.C., Lee Y.M., Lee J.Y., Lee P.J., Li K.C., Chen H.W., Yang P.C. Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat. Commun. 2014, 5:3472.
18. Lee K.W., Yeo S.Y., Sung C.O., Kim S.H. Twist1 is a key regulator of cancer-associated fibroblasts. Cancer Res. 2015, 75:73-85.
19. Jung Y., Kim J.K., Shiozawa Y., Wang J., Mishra A., Joseph J., Berry J.E., McGee S., Lee E., Sun H., Wang J., Jin T., Zhang H., Dai J., Krebsbach P.H., Keller E.T., Pienta K.J., Taichman R.S. Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat. Commun. 2013, 4:1795.
20. Maxwell P.J., Neisen J., Messenger J., Waugh D.J. Tumor-derived CXCL8 signaling augments stroma-derived CCL2-promoted proliferation and CXCL12-mediated invasion of PTEN-deficient prostate cancer cells. Oncotarget 2014, 5:4895-4908.
21. Kojima Y., Acar A., Eaton E.N., Mellody K.T., Scheel C., Ben-Porath I., Onder T.T., Wang Z.C., Richardson A.L., Weinberg R.A., Orimo A. Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc. Natl. Acad. Sci. U. S. A. 2010, 107:20009-20014.
22. Orimo A., Gupta P.B., Sgroi D.C., Arenzana-Seisdedos F., Delaunay T., Naeem R., Carey V.J., Richardson A.L., Weinberg R.A. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005, 121:335-348.
23. Yu Y., Xiao C.H., Tan L.D., Wang Q.S., Li X.Q., Feng Y.M. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-β signalling. Br. J. Cancer 2014, 110:724-732.
24. Calon A., Lonardo E., Berenguer-Llergo A., Espinet E., Hernando-Momblona X., Iglesias M., Sevillano M., Palomo-Ponce S., Tauriello D.V., Byrom D., Cortina C., Morral C., Barceló C., Tosi S., Riera A., Attolini C.S., Rossell D., Sancho E., Batlle E. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat. Genet. 2015, 47:320-329.
25. Calon A., Espinet E., Palomo-Ponce S., Tauriello D.V., Iglesias M., Céspedes M.V., Sevillano M., Nadal C., Jung P., Zhang X.H., Byrom D., Riera A., Rossell D., Mangues R., Massagué J., Sancho E., Batlle E. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell 2012, 22:571-584.
26. Tyan S.W., Kuo W.H., Huang C.K., Pan C.C., Shew J.Y., Chang K.J., Lee E.Y., Lee W.H. Breast cancer cells induce cancer-associated fibroblasts to secrete hepatocyte growth factor to enhance breast tumorigenesis. PLoS One 2011, 6(1):e15313.
27. Jia C.C., Wang T.T., Liu W., Fu B.S., Hua X., Wang G.Y., Li T.J., Li X., Wu X.Y., Tai Y., Zhou J., Chen G.H., Zhang Q. Cancer-associated fibroblasts from hepatocellular carcinoma promote malignant cell proliferation by HGF secretion. PLoS One 2013, 8:e63243.
28. Wu X., Chen X., Zhou Q., Li P., Yu B., Li J., Qu Y., Yan J., Yu Y., Yan M., Zhu Z., Liu B., Su L. Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. Cancer Lett. 2013, 335:128-135.
29. Saito S., Morishima K., Ui T., Hoshino H., Matsubara D., Ishikawa S., Aburatani H., Fukayama M., Hosoya Y., Sata N., Lefor A.K., Yasuda Y., Niki T. The role of HGF/MET and FGF/FGFR in fibroblast-derived growth stimulation and lapatinib-resistance of esophageal squamous cell carcinoma. BMC Cancer 2015, 15:82.
30. Luga V., Zhang L., Viloria-Petit A.M., Ogunjimi A.A., Inanlou M.R., Chiu E., Buchanan M., Hosein A.N., Basik M., Wrana J.L. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 2012, 151:1542-1556.
31. Camp J.T., Elloumi F., Roman-Perez E., Rein J., Stewart D.A., Harrell J.C., Perou C.M., Troester M.A. Interactions with fibroblasts are distinct in Basal-like and luminal breast cancers. Mol. Cancer Res. 2011, 9:3-13.
32. Otomo R., Otsubo C., Matsushima-Hibiya Y., Miyazaki M., Tashiro F., Ichikawa H., Kohno T., Ochiya T., Yokota J., Nakagama H., Taya Y., Enari M. TSPAN12 is a critical factor for cancer-fibroblast cell contact-mediated cancer invasion. Proc. Natl. Acad. Sci. U. S. A. 2014, 111:18691-18696.
33. Duda D.G., Duyverman A.M., Kohno M., Snuderl M., Steller E.J., Fukumura D., Jain R.K. Malignant cells facilitate lung metastasis by bringing their own soil. Proc. Natl. Acad. Sci. U. S. A. 2010, 107:21677-21682.
34. Arrigoni C., De Luca P., Gilardi M., Previdi S., Broggini M., Moretti M. Direct but not indirect co-culture with osteogenically differentiated human bone marrow stromal cells increases RANKL/OPG ratio in human breast cancer cells generating bone metastases. Mol. Cancer 2014, 13:238.
35. Kraman M., Bambrough P.J., Arnold J.N., Roberts E.W., Magiera L., Jones J.O., Gopinathan A., Tuveson D.A., Fearon D.T. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 2010, 330:827-830.
36. Feig C., Jones J.O., Kraman M., Wells R.J., Deonarine A., Chan D.S., Connell C.M., Roberts E.W., Zhao Q., Caballero O.L., Teichmann S.A., Janowitz T., Jodrell D.I., Tuveson D.A., Fearon D.T. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl. Acad. Sci. U. S. A. 2013, 110:20212-20217.
37. Kinoshita T., Ishii G., Hiraoka N., Hirayama S., Yamauchi C., Aokage K., Hishida T., Yoshida J., Nagai K., Ochiai A. Forkhead box P3 regulatory T cells coexisting with cancer associated fibroblasts are correlated with a poor outcome in lung adenocarcinoma. Cancer Sci. 2013, 104:409-415.
38. Erez N., Truitt M., Olson P., Arron S.T., Hanahan D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell 2010, 17:135-147.
39. Vosseler S., Lederle W., Airola K., Obermueller E., Fusenig N.E., Mueller M.M. Distinct progression-associated expression of tumor and stromal MMPs in HaCaT skin SCCs correlates with onset of invasion. Int. J. Cancer 2009, 125:2296-2306.
40. Boire A., Covic L., Agarwal A., Jacques S., Sherifi S., Kuliopulos A. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 2005, 120:303-313.
41. Gaggioli C., Hooper S., Hidalgo-Carcedo C., Grosse R., Marshall J.F., Harrington K., Sahai E. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 2007, 9:1392-1400.
42. Neri S., Ishii G., Hashimoto H., Kuwata T., Nagai K., Date H., Ochiai A. Podoplanin-expressing cancer-associated fibroblasts lead and enhance the local invasion of cancer cells in lung adenocarcinoma. Int. J. Cancer 2015, (Epub ahead of print).
43. Green J.L., La J., Yum K.W., Desai P., Rodewald L.W., Zhang X., Leblanc M., Nusse R., Lewis M.T., Wahl G.M. Paracrine Wnt signaling both promotes and inhibits human breast tumor growth. Proc. Natl. Acad. Sci. U. S. A. 2013, 110:6991-6996.
44. Akiri G., Cherian M.M., Vijayakumar S., Liu G., Bafico A., Aaronson S.A. Wnt pathway aberrations including autocrine Wnt activation occur at high frequency in human non-small-cell lung carcinoma. Oncogene 2009, 28:2163-2172.
45. Engle S.J., Hoying J.B., Boivin G.P., Ormsby I., Gartside P.S., Doetschman T. Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Res. 1999, 59:3379-3386.
46. Flaberg E., Markasz L., Petranyi G., Stuber G., Dicso F., Alchihabi N., Oláh È., Csízy I., Józsa T., Andrén O., Johansson J.E., Andersson S.O., Klein G., Szekely L. High-throughput live-cell imaging reveals differential inhibition of tumor cell proliferation by human fibroblasts. Int. J. Cancer 2011, 128:2793-2802.
47. Takahashi A., Ishii G., Neri S., Yoshida T., Hashimoto H., Suzuki S., Umemura S., Matsumoto S., Yoh K., Niho S., Goto K., Ohmatsu H., Nagai K., Gemma A., Ohe Y., Ochiai A. Podoplanin-expressing cancer-associated fibroblasts inhibit small cell lung cancer growth. Oncotarget 2015, 6:9531-9541.
48. Straussman R., Morikawa T., Shee K., Barzily-Rokni M., Qian Z.R., Du J., Davis A., Mongare M.M., Gould J., Frederick D.T., Cooper Z.A., Chapman P.B., Solit D.B., Ribas A., Lo R.S., Flaherty K.T., Ogino S., Wargo J.A., Golub T.R. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012, 487:500-504.
49. Wang W., Li Q., Yamada T., Matsumoto K., Matsumoto I., Oda M., Watanabe G., Kayano Y., Nishioka Y., Sone S., Yano S. Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Clin. Cancer Res. 2009, 15:6630-6638.
50. Yoshida T., Ishii G., Goto K., Neri S., Hashimoto H., Yoh K., Niho S., Umemura S., Matsumoto S., Ohmatsu H., Iida S., Niimi A., Nagai K., Ohe Y., Ochiai A. Podoplanin-positive cancer-associated fibroblasts in the tumor microenvironment induce primary resistance to EGFR-TKIs in lung adenocarcinoma with EGFR mutation. Clin. Cancer Res. 2015, 21:642-1651.
51. Yu Y., Xiao C.H., Tan L.D., Wang Q.S., Li X.Q., Feng Y.M. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-β signaling. Br. J. Cancer 2014, 110:724-732.
52. Hu Y., Yan C., Mu L., Huang K., Li X., Tao D., Wu Y., Qin J. Fibroblast-derived exosomes contribute to chemoresistance through priming cancer stem cells in colorectal cancer. PLoS One 2015, 10:e0125625.
53. Ramon A. Oncolytic adenoviruses in cancer treatment. Biomedicines 2014, 2:36-49.
54. Miyamoto H., Murakami T., Tsuchida K., Sugino H., Miyake H., Tashiro S. Tumor-stroma interaction of human pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas 2004, 28:38-44.
55. van der Kuip H., Goetz A.W., Miething C., Duyster J., Aulitzky W.E. Adhesion to fibronectin selectively protects Bcr-Abl+ cells from DNA damage-induced apoptosis. Blood 2001, 98:1532-1541.
56. Dangi-Garimella S., Krantz S.B., Barron M.R., Shields M.A., Heiferman M.J., Grippo P.J., Bentrem D.J., Munshi H.G. Three-dimensional collagen I promotes gemcitabine resistance in pancreatic cancer through MT1-MMP-mediated expression of HMGA2. Cancer Res. 2011, 71:1019-1028.
57. Dangi-Garimella S., Sahai V., Ebine K., Kumar K., Munshi H.G. Three-dimensional collagen I promotes gemcitabine resistance in vitro in pancreatic cancer cells through HMGA2-dependent histone acetyltransferase expression. PLoS One 2013, 8:e64566.
58. Provenzano P.P., Cuevas C., Chang A.E., Goel V.K., Von Hoff D.D., Hingorani S.R. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012, 21:418-429.
59. Sun Y., Campisi J., Higano C., Beer T.M., Porter P., Coleman I., True L., Nelson P.S. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat. Med. 2012, 18:1359-1368.
60. Lotti F1., Jarrar A.M., Pai R.K., Hitomi M., Lathia J., Mace A., Gantt G.A., Sukhdeo K., DeVecchio J., Vasanji A., Leahy P., Hjelmeland A.B., Kalady M.F., Rich J.N. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J. Exp. Med. 2013, 210:2851-2872.
61. Shekhar M.P., Santner S., Carolin K.A., Tait L. Direct involvement of breast tumor fibroblasts in the modulation of tamoxifen sensitivity. Am. J. Pathol. 2007, 170:1546-1560.
62. Martinez-Outschoorn U.E., Goldberg A., Lin Z., Ko Y.H., Flomenberg N., Wang C., Pavlides S., Pestell R.G., Howell A., Sotgia F., Lisanti M.P. Anti-estrogen resistance in breast cancer is induced by the tumor microenvironment and can be overcome by inhibiting mitochondrial function in epithelial cancer cells. Cancer Biol. Ther. 2011, 12:924-938.
63. Lafkas D., Trimis G., Papavassiliou A.G., Kiaris H. P53 mutations in stromal fibroblasts sensitize tumors against chemotherapy. Int. J. Cancer 2008, 123:967-971.
64. Dittmer A., Fuchs A., Oerlecke I., Leyh B., Kaiser S., Martens J.W., Lützkendorf J., Müller L., Dittmer J. Mesenchymal stem cells and carcinoma-associated fibroblasts sensitize breast cancer cells in 3D cultures to kinase inhibitors. Int. J. Oncol. 2011, 39:689-696.
65. Loeffler M., Krüger J.A., Niethammer A.G., Reisfeld R.A. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J. Clin. Invest. 2006, 116:1955-1962.
66. Mertens J.C., Fingas C.D., Christensen J.D., Smoot R.L., Bronk S.F., Werneburg N.W., Gustafson M.P., Dietz A.B., Roberts L.R., Sirica A.E., Gores G.J. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res. 2013, 73:897-907.
67. Olive K.P., Jacobetz M.A., Davidson C.J., Gopinathan A., McIntyre D., Honess D., Madhu B., Goldgraben M.A., Caldwell M.E., Allard D., Frese K.K., Denicola G., Feig C., Combs C., Winter S.P., Ireland-Zecchini H., Reichelt S., Howat W.J., Chang A., Dhara M., Wang L., Rückert F., Grützmann R., Pilarsky C., Izeradjene K., Hingorani S.R., Huang P., Davies S.E., Plunkett W., Egorin M., Hruban R.H., Whitebread N., McGovern K., Adams J., Iacobuzio-Donahue C., Griffiths J., Tuveson D.A. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009, 324:1457-1461.
68. Sherman M.H., Yu R.T., Engle D.D., Ding N., Atkins A.R., Tiriac H., Collisson E.A., Connor F., Van Dyke T., Kozlov S., Martin P., Tseng T.W., Dawson D.W., Donahue T.R., Masamune A., Shimosegawa T., Apte M.V., Wilson J.S., Ng B., Lau S.L., Gunton J.E., Wahl G.M., Hunter T., Drebin J.A., O'Dwyer P.J., Liddle C., Tuveson D.A., Downes M., Evans R.M. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell Sep 25 2014, 159(1):80-93.
69. Yasunaga M., Manabe S., Tarin D., Matsumura Y. Cancer-stroma targeting therapy by cytotoxic immunoconjugate bound to the collagen 4 network in the tumor tissue. Bioconjug. Chem. 2011, 22:1776-1783.
70. Yasunaga M., Manabe S., Tarin D., Matsumura Y. Tailored immunoconjugate therapy depending on a quantity of tumor stroma. Cancer Sci. 2013, 104:231-237.
71. Ishii G., Sangai T., Ito T., Hasebe T., Endoh Y., Sasaki H., Harigaya K., Ochiai A. In vivo and in vitro characterization of human fibroblasts recruited selectively into human cancer stroma. Int. J. Cancer 2005, 117:212-220.