Abstract
Conventional and targeted chemotherapies remain integral strategies to treat solid tumors. Despite the large number of anti-cancer drugs available, chemotherapy does not completely eradicate disease. Disease recurrence and the growth of drug resistant tumors remain significant problems in anti-cancer treatment. To develop more effective treatment strategies, it is important to understand the underlying cellular and molecular mechanisms of drug resistance. It is generally accepted that cancer cells do not function alone, but evolve through interactions with the surrounding tumor microenvironment. As key cellular components of the tumor microenvironment, fibroblasts regulate the growth and progression of many solid tumors. Emerging studies demonstrate that fibroblasts secrete a multitude of factors that enable cancer cells to become drug resistant. This review will explore how fibroblast secretion of soluble factors act on cancer cells to enhance cancer cell survival and cancer stem cell renewal, contributing to the development of drug resistant cancer.
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Ablett M P O B C, Sims A H, Farnie G, Clarke R B (2013). A differential role for CXCR4 in the regulation of normal versus malignant breast stem cell activity. OncotargetEpub.
Adams D J, Knick V C (1995). P-glycoprotein mediated resistance to 5′-nor-anhydro-vinblastine (Navelbine). Invest New Drugs, 13(1): 13–21
Addadi Y, Moskovits N, Granot D, Lozano G, Carmi Y, Apte R N, Neeman M, Oren M (2010). p53 status in stromal fibroblasts modulates tumor growth in an SDF1-dependent manner. Cancer Res, 70(23): 9650–9658
Aguirre-Ghiso J A, Ossowski L, Rosenbaum S K (2004). Green fluorescent protein tagging of extracellular signal-regulated kinase and p38 pathways reveals novel dynamics of pathway activation during primary and metastatic growth. Cancer Res, 64(20): 7336–7345
Ahn S, Cho J, Sung J, Lee J E, Nam S J, Kim K M, Cho E Y (2012). The prognostic significance of tumor-associated stroma in invasive breast carcinoma. Tumour Biol, 33(5): 1573–1580
Aishima S, Taguchi K, Terashi T, Matsuura S, Shimada M, and Tsuneyoshi M (2003). Tenascin expression at the invasive front is associated with poor prognosis in intrahepatic cholangiocarcinoma. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc 16(10), 1019–1027
Allavena P, Germano G, Marchesi F, Mantovani A (2011). Chemokines in cancer related inflammation. Exp Cell Res, 317(5): 664–673
Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, Porter D, Hu M, Chin L, Richardson A, Schnitt S, Sellers W R, Polyak K (2004). Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell, 6(1): 17–32
Amar S, Roy V, Perez E A (2009). Treatment of metastatic breast cancer: looking towards the future. Breast Cancer Res Treat, 114(3): 413–422
Anastas J N, Moon R T (2013). WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer, 13(1): 11–26
Astsaturov I, Ratushny V, Sukhanova A, Einarson M B, Bagnyukova T, Zhou Y, Devarajan K, Silverman J S, Tikhmyanova N, Skobeleva N, Pecherskaya A, Nasto R E, Sharma C, Jablonski S A, Serebriiskii I G, Weiner L M, Golemis E A (2010). Synthetic lethal screen of an EGFR-centered network to improve targeted therapies. Sci Signal, 3(140): ra67
Ayala G, Tuxhorn J A, Wheeler T M, Frolov A, Scardino P T, Ohori M, Wheeler M, Spitler J, Rowley D R (2003). Reactive stroma as a predictor of biochemical-free recurrence in prostate cancer. Clin Cancer Res, 9(13): 4792–4801
Balkwill F R (2012). The chemokine system and cancer. J Pathol, 226(2): 148–157
Balkwill F R, Mantovani A (2012). Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol, 22(1): 33–40
Bao L, Haque A, Jackson K, Hazari S, Moroz K, Jetly R, Dash S (2011). Increased expression of P-glycoprotein is associated with doxorubicin chemoresistance in the metastatic 4T1 breast cancer model. Am J Pathol, 178(2): 838–852
Bao S, Ouyang G, Bai X, Huang Z, Ma C, Liu M, Shao R, Anderson R M, Rich J N, Wang X F (2004). Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway. Cancer Cell, 5(4): 329–339
Baril P, Gangeswaran R, Mahon P C, Caulee K, Kocher H M, Harada T, Zhu M, Kalthoff H, Crnogorac-Jurcevic T, and Lemoine N R (2007). Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the beta4 integrin and the PI3k pathway. Oncogene 26(14), 2082–2094
Bielen H, Houart C (2014). The Wnt Cries Many: Wnt regulation of neurogenesis through tissue patterning, proliferation and asymmetric cell division. Dev Neurobiol, doi: 10.1002/dneu.22168
Binaschi M, Supino R, Gambetta R A, Giaccone G, Prosperi E, Capranico G, Cataldo I, Zunino F (1995). MRP gene overexpression in a human doxorubicin-resistant SCLC cell line: alterations in cellular pharmacokinetics and in pattern of cross-resistance. Int J Cancer, 62(1): 84–89
Brellier F, Chiquet-Ehrismann R (2012). How do tenascins influence the birth and life of a malignant cell? J Cell Mol Med, 16(1): 32–40
Brewster A M, Hortobagyi G N, Broglio K R, Kau S W, Santa-Maria C A, Arun B, Buzdar A U, Booser D J, Valero V, Bondy M, Esteva F J (2008). Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst, 100(16): 1179–1183
Brunner A, Mayerl C, Tzankov A, Verdorfer I, Tschörner I, Rogatsch H, Mikuz G (2004). Prognostic significance of tenascin-C expression in superficial and invasive bladder cancer. J Clin Pathol, 57(9): 927–931
Buck M B, Pfizenmaier K, Knabbe C (2004). Antiestrogens induce growth inhibition by sequential activation of p38 mitogen-activated protein kinase and transforming growth factor-beta pathways in human breast cancer cells. Mol Endocrinol, 18(7): 1643–1657
Burger J A, and Kipps T J (2006). CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood, 107(5): 1761–1767
Busam K J (2011). Desmoplastic melanoma. Clin Lab Med, 31(2): 321–330
Buyukbayram H, Arslan A (2002). Value of tenascin-C content and association with clinicopathological parameters in uterine cervical lesions. Int J Cancer, 100(6): 719–722
Camps J L, Chang S M, Hsu T C, Freeman M R, Hong S J, Zhau H E, von Eschenbach A C, Chung L W (1990). Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc Natl Acad Sci USA, 87(1): 75–79
Cecchi F, Rabe D C, Bottaro D P (2010). Targeting the HGF/Met signalling pathway in cancer. Eur J Cancer, 46(7): 1260–1270
Chao C, Carmical J R, Ives K L, Wood T G, Aronson J F, Gomez G A, Djukom C D, Hellmich M R (2012). CD133 + colon cancer cells are more interactive with the tumor microenvironment than CD133-cells. Lab Invest, 92(3): 420–436
Chen J T, Huang C Y, Chiang Y Y, Chen W H, Chiou S H, Chen C Y, Chow K C (2008). HGF increases cisplatin resistance via downregulation of AIF in lung cancer cells. Am J Respir Cell Mol Biol, 38(5): 559–565
Chen S S, Lee L (1984). Prognostic significance of morphology of tumor and retroperitoneal lymph nodes in epithelial carcinoma of the ovary. II. Correlation with survival. Gynecol Oncol, 18(1): 94–99
Choi K U, Yun J S, Lee I H, Heo S C, Shin S H, Jeon E S, Choi Y J, Suh D S, Yoon M S, Kim J H (2011). Lysophosphatidic acid-induced expression of periostin in stromal cells: Prognoistic relevance of periostin expression in epithelial ovarian cancer. Int J Cancer, 128(2): 332–342
Cohen M, Marchand-Adam S, Lecon-Malas V, Marchal-Somme J, Boutten A, Durand G, Crestani B, Dehoux M (2006). HGF synthesis in human lung fibroblasts is regulated by oncostatin M. Am J Physiol Lung Cell Mol Physiol, 290(6): L1097–L1103
Cohen S J, Alpaugh R K, Palazzo I, Meropol N J, Rogatko A, Xu Z, Hoffman J P, Weiner L M, Cheng J D (2008). Fibroblast activation protein and its relationship to clinical outcome in pancreatic adenocarcinoma. Pancreas, 37(2): 154–158
Conklin M W, Keely P J (2012). Why the stroma matters in breast cancer: insights into breast cancer patient outcomes through the examination of stromal biomarkers. Cell Adhes Migr, 6(3): 249–260
Conti I, Rollins B J (2004). CCL2 (monocyte chemoattractant protein-1) and cancer. Semin Cancer Biol, 14(3): 149–154
Dačević M, Isaković A, Podolski-Renić A, Isaković A M, Stanković T, Milošević Z, Rakić L, Ruždijić S, Pešić M (2013). Purine nucleoside analog-sulfinosine modulates diverse mechanisms of cancer progression in multi-drug resistant cancer cell lines. PLoS ONE, 8(1): e54044
Daly A J, McIlreavey L, Irwin C R (2008). Regulation of HGF and SDF-1 expression by oral fibroblasts-implications for invasion of oral cancer. Oral Oncol, 44(7): 646–651
de Boer R A, van Veldhuisen D J, Gansevoort R T, Muller Kobold A C, van Gilst W H, Hillege H L, Bakker S J, van der Harst P (2012). The fibrosis marker galectin-3 and outcome in the general population. J Intern Med, 272(1): 55–64
de Boussac H, Orbán T I, Várady G, Tihanyi B, Bacquet C, Brózik A, Váradi A, Sarkadi B, Arányi T (2012). Stimulus-induced expression of the ABCG2 multidrug transporter in HepG2 hepatocarcinoma model cells involves the ERK1/2 cascade and alternative promoters. Biochem Biophys Res Commun, 426(2): 172–176
De Wever O, Nguyen Q D, Van Hoorde L, Bracke M, Bruyneel E, Gespach C, Mareel M (2004). Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J, 18(9): 1016–1018
Dean M (2009). ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia, 14(1): 3–9
Deng B, Huang W, Tan Q Y, Fan X Q, Jiang Y G, Liu L, Zhong Y Y, Liang Y G, Wang R W (2011). Breast cancer anti-estrogen resistance protein 1 (BCAR1/p130cas) in pulmonary disease tissue and serum. Mol Diagn Ther, 15(1): 31–40
DeVita V T Jr, Chu E (2008). A history of cancer chemotherapy. Cancer Res, 68(21): 8643–8653
Diah S K, Smitherman P K, Aldridge J, Volk E L, Schneider E, Townsend A J, Morrow C S (2001). Resistance to mitoxantrone in multidrug-resistant MCF7 breast cancer cells: evaluation of mitoxantrone transport and the role of multidrug resistance protein family proteins. Cancer Res, 61(14): 5461–5467
Diaz L A, Jr., Williams R T, Wu J, Kinde I, Hecht J R, Berlin J, Allen B, Bozic I, Reiter J G, Nowak M A, Kinzler K W, Oliner K S, and Vogelstein B (2012). The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486(7404), 537–540
Domanska U M, Timmer-Bosscha H, Nagengast W B, Oude Munnink T H, Kruizinga R C, Ananias H J, Kliphuis NM, Huls G, De Vries E G, de Jong I J, Walenkamp A M (2012). CXCR4 inhibition with AMD3100 sensitizes prostate cancer to docetaxel chemotherapy. Neoplasia, 14(8): 709–718
Dubrovska A, Elliott J, Salamone R J, Telegeev G D, Stakhovsky A E, Schepotin I B, Yan F, Wang Y, Bouchez L C, Kularatne S A, Watson J, Trussell C, Reddy V A, Cho C Y, Schultz P G (2012). CXCR4 expression in prostate cancer progenitor cells. PLoS ONE, 7(2): e31226
Earp H S, Dawson T L, Li X, Yu H (1995). Heterodimerization and functional interaction between EGF receptor family members: a new signaling paradigm with implications for breast cancer research. Breast Cancer Res Treat, 35(1): 115–132
Emoto K, Yamada Y, Sawada H, Fujimoto H, Ueno M, Takayama T, Kamada K, Naito A, Hirao S, and Nakajima Y (2001). Annexin II overexpression correlates with stromal tenascin-C overexpression: a prognostic marker in colorectal carcinoma. Cancer, 92(6): 1419–1426
Erbas B, Provenzano E, Armes J, Gertig D (2006). The natural history of ductal carcinoma in situ of the breast: a review. Breast Cancer Res Treat, 97(2): 135–144
Eyman D, Damodarasamy M, Plymate S R, Reed M J (2009). CCL5 secreted by senescent aged fibroblasts induces proliferation of prostate epithelial cells and expression of genes that modulate angiogenesis. J Cell Physiol, 220(2): 376–381
Fang W B, Jokar I, Zou A, Lambert D, Dendukuri P, Cheng N (2012). CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogenactivated protein kinase (MAPK)-dependent mechanisms. J Biol Chem, 287(43): 36593–36608
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 (2013). Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA, 110(50): 20212–20217
Flaherty K T, Puzanov I, Kim K B, Ribas A, McArthur G A, Sosman J A, O’Dwyer P J, Lee R J, Grippo J F, Nolop K, Chapman P B (2010). Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med, 363(9): 809–819
Fleming J M, Miller T C, Kidacki M, Ginsburg E, Stuelten C H, Stewart D A, Troester M A, Vonderhaar B K (2012). Paracrine interactions between primary human macrophages and human fibroblasts enhance murine mammary gland humanization in vivo. Breast Cancer Res, 14(3): R97
Foley J, Nickerson N K, Nam S, Allen K T, Gilmore J L, Nephew K P, Riese D J 2nd (2010). EGFR signaling in breast cancer: bad to the bone. Semin Cell Dev Biol, 21(9): 951–960
Fujimoto H, Sangai T, Ishii G, Ikehara A, Nagashima T, Miyazaki M, Ochiai A (2009). Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer, 125(6): 1276–1284
Fukunaga-Kalabis M, Martinez G, Nguyen T K, Kim D, Santiago-Walker A, Roesch A, and Herlyn M (2010). Tenascin-C promotes melanoma progression by maintaining the ABCB5-positive side population. Oncogene, 29(46): 6115–6124
Gao C F, Vande Woude G F (2005). HGF/SF-Met signaling in tumor progression. Cell Res, 15(1): 49–51
Gillan L, Matei D, Fishman D A, Gerbin C S, Karlan B Y, Chang D D (2002). Periostin secreted by epithelial ovarian carcinoma is a ligand for alpha(V)beta(3) and alpha(V)beta(5) integrins and promotes cell motility. Cancer Res, 62(18): 5358–5364
Goldberg R M (2006). Intensive surveillance after stage II or III colorectal cancer: is it worth it? J Clin Oncol, 24(3): 330–331
Gong X G, Lv Y F, Li X Q, Xu F G, Ma Q Y (2010). Gemcitabine resistance induced by interaction between alternatively spliced segment of tenascin-C and annexin A2 in pancreatic cancer cells. Biol Pharm Bull, 33(8): 1261–1267
Guirouilh J, Castroviejo M, Balabaud C, Desmouliere A, Rosenbaum J (2000). Hepatocarcinoma cells stimulate hepatocyte growth factor secretion in human liver myofibroblasts. Int J Oncol, 17(4): 777–781
Gupta V, Bassi D E, Simons J D, Devarajan K, Al-Saleem T, Uzzo R G, Cukierman E (2011). Elevated expression of stromal palladin predicts poor clinical outcome in renal cell carcinoma. PLoS ONE, 6(6): e21494
Hasebe T, Mukai K, Tsuda H, Ochiai A (2000). New prognostic histological parameter of invasive ductal carcinoma of the breast: clinicopathological significance of fibrotic focus. Pathol Int, 50(4): 263–272
Heidelberger C, Chaudhuri N K, Danneberg P, Mooren D, Griesbach L, Duschinsky R, Schnitzer R J, Pleven E, Scheiner J (1957). Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature, 179(4561): 663–666
Hembruff S L, Jokar I, Yang L, Cheng N (2010). Loss of transforming growth factor-beta signaling in mammary fibroblasts enhances CCL2 secretion to promote mammary tumor progression through macrophage-dependent and-independent mechanisms. Neoplasia, 12(5): 425–433
Hermann P C, Huber S L, Herrler T, Aicher A, Ellwart J W, Guba M, Bruns C J, Heeschen C (2007). Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell, 1(3): 313–323
Herrera M, Herrera A, Domínguez G, Silva J, García V, García J M, Gómez I, Soldevilla B, Muñoz C, Provencio M, Campos-Martin Y, García de Herreros A, Casal I, Bonilla F, Peña C (2013). Cancerassociated fibroblast and M2 macrophage markers together predict outcome in colorectal cancer patients. Cancer Sci, 104(4): 437–444
Hidalgo M (2010). Pancreatic cancer. N Engl J Med, 362(17): 1605–1617
Holohan C, Van Schaeybroeck S, Longley D B, Johnston P G (2013). Cancer drug resistance: an evolving paradigm. Nat Rev Cancer, 13(10): 714–726
Hong L Z, Wei X W, Chen J F, Shi Y (2013). Overexpression of periostin predicts poor prognosis in non-small cell lung cancer. Oncol Lett, 6(6):1595–1603
Ibarra-Drendall C, Dietze E C, Seewaldt V L (2011). Metabolic syndrome and breast cancer risk: Is there a role for metformin? Current Breast Cancer Rep, 3(3): 142–150
Ilmonen S, Jahkola T, Turunen J P, Muhonen T, Asko-Seljavaara S (2004). Tenascin-C in primary malignant melanoma of the skin. Histopathology, 45(4): 405–411
Jahkola T, Toivonen T, Virtanen I, von Smitten K, Nordling S, von Boguslawski K, Haglund C, Nevanlinna H, Blomqvist C (1998). Tenascin-C expression in invasion border of early breast cancer: a predictor of local and distant recurrence. Br J Cancer, 78(11): 1507–1513
Jin J, Huang M, Wei H L, Liu G T (2002). Mechanism of 5-fluorouracil required resistance in human hepatocellular carcinoma cell line Bel (7402). World J Gastroenterol, 8(6): 1029–1034
Kahn N, Meister M, Eberhardt R, Muley T, Schnabel P A, Bender C, Johannes M, Keitel D, Sultmann H, Herth F J, Kuner R (2012). Early detection of lung cancer by molecular markers in endobronchial epithelial-lining fluid. J Thoracic Oncol, 7(6): 1001–1008
Kalluri R, Zeisberg M (2006). Fibroblasts in cancer. Nat Rev Cancer, 6(5): 392–401
Kaseda K, Ishii G, Aokage K, Takahashi A, Kuwata T, Hishida T, Yoshida J, Kohno M, Nagai K, Ochiai A (2013). Identification of intravascular tumor microenvironment features predicting the recurrence of pathological stage I lung adenocarcinoma. Cancer Sci, 104(9): 1262–1269
Kawashiri S, Tanaka A, Noguchi N, Hase T, Nakaya H, Ohara T, Kato K, Yamamoto E (2009). Significance of stromal desmoplasia and myofibroblast appearance at the invasive front in squamous cell carcinoma of the oral cavity. Head Neck, 31(10): 1346–1353
Keizer H G, Schuurhuis G J, Broxterman H J, Lankelma J, Schoonen W G, van Rijn J, Pinedo HM, Joenje H (1989). Correlation of multidrug resistance with decreased drug accumulation, altered subcellular drug distribution, and increased P-glycoprotein expression in cultured SW-1573 human lung tumor cells. Cancer Res, 49(11): 2988–2993
Kemp L E, Mulloy B, Gherardi E (2006). Signalling by HGF/SF and Met: the role of heparan sulphate co-receptors. Biochem Soc Trans, 34(Pt 3): 414–417
Khunamornpong S, Lekawanvijit S, Settakorn J, Sukpan K, Suprasert P, Siriaunkgul S (2013). Prognostic model in patients with early-stage squamous cell carcinoma of the uterine cervix: a combination of invasive margin pathological characteristics and lymphovascular space invasion. Asian Pac J Cancer Prev, 14(11): 6935–6940
Kii I, Nishiyama T, Li M, Matsumoto K, Saito M, Amizuka N, Kudo A (2010). Incorporation of tenascin-C into the extracellular matrix by periostin underlies an extracellular meshwork architecture. J Biol Chem, 285(3): 2028–2039
Kitano H, Kageyama S, Hewitt S M, Hayashi R, Doki Y, Ozaki Y, Fujino S, Takikita M, Kubo H, Fukuoka J (2010). Podoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survival. Arch Pathol Lab Med, 134(10): 1520–1527
Kojima M, Nakajima K, Ishii G, Saito N, Ochiai A (2010). Peritoneal elastic laminal invasion of colorectal cancer: the diagnostic utility and clinicopathologic relationship. Am J Surg Pathol, 34(9): 1351–1360
Kreuzaler P, Watson C J (2012). Killing a cancer: what are the alternatives? Nat Rev Cancer, 12(6): 411–424
Kucia M, Jankowski K, Reca R, Wysoczynski M, Bandura L, Allendorf D J, Zhang J, Ratajczak J, Ratajczak M Z (2004). CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol, 35(3): 233–245
Kwon Y, Smith B D, Zhou Y, Kaufman M D, Godwin A K (2013). Effective inhibition of c-MET-mediated signaling, growth and migration of ovarian cancer cells is influenced by the ovarian tissue microenvironment. Oncogene
Lari S A, Kuerer H M (2011). Biological Markers in DCIS and Risk of Breast Recurrence: A Systematic Review. J Cancer, 2: 232–261
Lee S H, Kim H, Hwang J H, Lee H S, Cho J Y, Yoon Y S, Han H S (2012). Breast cancer resistance protein expression is associated with early recurrence and decreased survival in resectable pancreatic cancer patients. Pathol Int, 62(3): 167–175
Lemmon M A, and Schlessinger J (2010). Cell signaling by receptor tyrosine kinases. Cell, 141(7): 1117–1134
Lengauer C, Kinzler KW, and Vogelstein B (1998). Genetic instabilities in human cancers. Nature, 396(6712): 643–649
Levina V, Marrangoni A M, DeMarco R, Gorelik E, Lokshin A E (2008). Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties. PLoS ONE, 3(8): e3077
Lhommé C, Joly F, Walker J L, Lissoni A A, Nicoletto MO, Manikhas G M, Baekelandt M M, Gordon A N, Fracasso P M, Mietlowski W L, Jones G J, Dugan M H (2008). Phase III study of valspodar (PSC 833) combined with paclitaxel and carboplatin compared with paclitaxel and carboplatin alone in patients with stage IV or suboptimally debulked stage III epithelial ovarian cancer or primary peritoneal cancer. J Clin Oncol, 26(16): 2674–2682
Li L, Dragulev B, Zigrino P, Mauch C, Fox J W (2009). The invasive potential of human melanoma cell lines correlates with their ability to alter fibroblast gene expression in vitro and the stromal microenvironment in vivo. Int J Cancer, 125(8): 1796–1804
Li M, Li C, Li D, Xie Y, Shi J, Li G, Guan Y, Li M, Zhang P, Peng F, Xiao Z, Chen Z (2012). Periostin, a stroma-associated protein, correlates with tumor invasiveness and progression in nasopharyngeal carcinoma. Clin Exp Metastasis, 29(8): 865–877
Liao D, Luo Y, Markowitz D, Xiang R, Reisfeld R A (2009). Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS ONE, 4(11): e7965
Lim K P, Cirillo N, Hassona Y, Wei W, Thurlow J K, Cheong S C, Pitiyage G, Parkinson E K, Prime S S (2011). Fibroblast gene expression profile reflects the stage of tumour progression in oral squamous cell carcinoma. J Pathol, 223(4): 459–469
Liu R, Li J, Xie K, Zhang T, Lei Y, Chen Y, Zhang L, Huang K, Wang K, Wu H, Wu M, Nice E C, Huang C, Wei Y (2013). FGFR4 promotes stroma-induced epithelial-to-mesenchymal transition in colorectal cancer. Cancer Res, 73(19): 5926–5935
Loebinger M R, Giangreco A, Groot K R, Prichard L, Allen K, Simpson C, Bazley L, Navani N, Tibrewal S, Davies D, Janes S M (2008). Squamous cell cancers contain a side population of stem-like cells that are made chemosensitive by ABC transporter blockade. Br J Cancer, 98(2): 380–387
Lotti F, Jarrar A M, Pai R K, Hitomi M, Lathia J, Mace A, Gantt G A Jr, Sukhdeo K, DeVecchio J, Vasanji A, Leahy P, Hjelmeland A B, Kalady M F, Rich J N (2013). Chemotherapy activates cancerassociated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med, 210(13): 2851–2872
Lu Y, Chen Q, Corey E, Xie W, Fan J, Mizokami A, Zhang J (2009). Activation of MCP-1/CCR2 axis promotes prostate cancer growth in bone. Clin Exp Metastasis, 26(2): 161–169
Lu Y, Xiao G, Galson D L, Nishio Y, Mizokami A, Keller E T, Yao Z, Zhang J (2007). PTHrP-induced MCP-1 production by human bone marrow endothelial cells and osteoblasts promotes osteoclast differentiation and prostate cancer cell proliferation and invasion in vitro. Int J Cancer, 121(4): 724–733
Lv Y, Wang W, Jia W D, Sun Q K, Li J S, Ma J L, Liu W B, Zhou H C, Ge Y S, Yu J H, Xia H H, Xu G L (2013). High-level expression of periostin is closely related to metastatic potential and poor prognosis of hepatocellular carcinoma. Med Oncol, 30(1): 385
MacDonald B T, Tamai K, He X (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell, 17(1): 9–26
Malanchi I, Santamaria-Martinez A, Susanto E, Peng H, Lehr H A, Delaloye J F, Huelsken J (2012). Interactions between cancer stem cells and their niche govern metastatic colonization. Nature, 481(7379): 85–89
Malofeeva E V, Domanitskaya N, Gudima M, Hopper-Borge E A (2012). Modulation of the ATPase and transport activities of broadacting multidrug resistance factor ABCC10 (MRP7). Cancer Res, 72(24): 6457–6467
Marsh D, Suchak K, Moutasim K A, Vallath S, Hopper C, Jerjes W, Upile T, Kalavrezos N, Violette S M, Weinreb P H, Chester K A, Chana J S, Marshall J F, Hart I R, Hackshaw A K, Piper K, Thomas G J (2011). Stromal features are predictive of disease mortality in oral cancer patients. J Pathol, 223(4): 470–481
Masuoka M, Shiraishi H, Ohta S, Suzuki S, Arima K, Aoki S, Toda S, Inagaki N, Kurihara Y, Hayashida S, Takeuchi S, Koike K, Ono J, Noshiro H, Furue M, Conway S J, Narisawa Y, Izuhara K (2012). Periostin promotes chronic allergic inflammation in response to Th2 cytokines. J Clin Invest, 122(7): 2590–2600
Mertens J C, Fingas C D, Christensen J D, Smoot R L, Bronk S F, Werneburg NW, Gustafson MP, Dietz A B, Roberts L R, Sirica A E, Gores G J (2013). Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res, 73(2): 897–907
Mhawech-Fauceglia P, Wang D, Samrao D, Kim G, Lawrenson K, Meneses T, Liu S, Yessaian A, Pejovic T (2013). Clinical implications of marker expression of carcinoma-associated Fibroblasts (CAFs) in patients with epithelial ovarian carcinoma after treatment with neoadjuvant chemotherapy. Cancer Microenviron, PMID: 24214412
Millward M J, Cantwell B M, Munro N C, Robinson A, Corris P A, Harris A L (1993). Oral verapamil with chemotherapy for advanced non-small cell lung cancer: a randomised study. Br J Cancer, 67(5): 1031–1035
Mueller L, von Seggern L, Schumacher J, Goumas F, Wilms C, Braun F, Broering D C (2010). TNF-alpha similarly induces IL-6 and MCP-1 in fibroblasts from colorectal liver metastases and normal liver fibroblasts. Biochem Biophys Res Commun, 397(3): 586–591
Naldini L, Weidner K M, Vigna E, Gaudino G, Bardelli A, Ponzetto C, Narsimhan R P, Hartmann G, Zarnegar R, Michalopoulos G K, et al (1991). Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J, 10(10): 2867–2878
Naumov G N, Townson J L, MacDonald I C, Wilson S M, Bramwell V H, Groom A C, Chambers A F (2003). Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or latedeveloping metastases. Breast Cancer Res Treat, 82(3): 199–206
Nicolo G, Salvi S, Oliveri G, Borsi L, Castellani P, Zardi L (1990). Expression of tenascin and of the ED-B containing oncofetal fibronectin isoform in human cancer. Cell Differ Dev, 32(3): 401–408
Nuzzo P V, Rubagotti A, Zinoli L, Ricci F, Salvi S, Boccardo S, Boccardo F (2012). Prognostic value of stromal and epithelial periostin expression in human prostate cancer: correlation with clinical pathological features and the risk of biochemical relapse or death. BMC Cancer, 12(1): 625
O’Connell J T, Sugimoto H, Cooke V G, MacDonald B A, Mehta A I, LeBleu V S, Dewar R, Rocha R M, Brentani R R, Resnick M B, Neilson E G, Zeisberg M, Kalluri R (2011). VEGF-A and Tenascin-C produced by S100A4 + stromal cells are important for metastatic colonization. Proc Natl Acad Sci USA, 108(38): 16002–16007
Oguri T, Ozasa H, Uemura T, Bessho Y, Miyazaki M, Maeno K, Maeda H, Sato S, Ueda R (2008). MRP7/ABCC10 expression is a predictive biomarker for the resistance to paclitaxel in non-small cell lung cancer. Mol Cancer Ther, 7(5): 1150–1155
Ohira S, Sasaki M, Harada K, Sato Y, Zen Y, Isse K, Kozaka K, Ishikawa A, Oda K, Nimura Y, Nakanuma Y (2006). Possible regulation of migration of intrahepatic cholangiocarcinoma cells by interaction of CXCR4 expressed in carcinoma cells with tumor necrosis factor-alpha and stromal-derived factor-1 released in stroma. Am J Pathol, 168(4): 1155–1168
Ohnishi T, Daikuhara Y (2003). Hepatocyte growth factor/scatter factor in development, inflammation and carcinogenesis: its expression and role in oral tissues. Arch Oral Biol, 48(12): 797–804
Ohno Y, Izumi M, Yoshioka K, Ohori M, Yonou H, Tachibana M (2008). Prognostic significance of tenascin-C expression in clear cell renal cell carcinoma. Oncol Rep, 20(3): 511–516
Olumi A F, Grossfeld G D, Hayward SW, Carroll P R, Tlsty T D, Cunha G R (1999). Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res, 59(19): 5002–5011
Orend G, Chiquet-Ehrismann R (2006). Tenascin-C induced signaling in cancer. Cancer Lett, 244(2): 143–163
Orimo A, Gupta P B, Sgroi D C, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey V J, Richardson A L, Weinberg R A (2005). Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 121(3): 335–348
Oskarsson T, Acharyya S, Zhang X H, Vanharanta S, Tavazoie S F, Morris P G, Downey R J, Manova-Todorova K, Brogi E, Massagué J (2011). Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med, 17(7): 867–874
Ostman A, Augsten M (2009). Cancer-associated fibroblasts and tumor growth-bystanders turning into key players. Curr Opin Genet Dev, 19(1): 67–73
Parr C, Jiang W G (2001). Expression of hepatocyte growth factor/ scatter factor, its activator, inhibitors and the c-Met receptor in human cancer cells. Int J Oncol, 19(4): 857–863
Paulsson J, Sjöblom T, Micke P, Pontén F, Landberg G, Heldin C H, Bergh J, Brennan D J, Jirström K, Ostman A (2009). Prognostic significance of stromal platelet-derived growth factor beta-receptor expression in human breast cancer. Am J Pathol, 175(1): 334–341
Peled A, and Tavor S (2013). Role of CXCR4 in the pathogenesis of acute myeloid leukemia. Theranostics 3(1), 34–39.
Pezzolo A, Parodi F, Marimpietri D, Raffaghello L, Cocco C, Pistorio A, Mosconi M, Gambini C, Cilli M, Deaglio S, Malavasi F, Pistoia V (2011). Oct-4 +/Tenascin C + neuroblastoma cells serve as progenitors of tumor-derived endothelial cells. Cell Res, 21(10): 1470–1486
Polanska U M, Orimo A (2013). Carcinoma-associated fibroblasts: nonneoplastic tumour-promoting mesenchymal cells. J Cell Physiol, 228(8): 1651–1657
Polyak K, Kalluri R (2010). The role of the microenvironment in mammary gland development and cancer. Cold Spring Harb Perspect Biol, 2(11): a003244
Qian B Z, Li J, Zhang H, Kitamura T, Zhang J, Campion L R, Kaiser E A, Snyder L A, and Pollard J W (2011). CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475(7355), 222–225.
Qian D Z, Rademacher B L, Pittsenbarger J, Huang C Y, Myrthue A, Higano C S, Garzotto M, Nelson P S, and Beer T M (2010). CCL2 is induced by chemotherapy and protects prostate cancer cells from docetaxel-induced cytotoxicity. Prostate, 70(4): 433–442
Roberts P J, and Der C J (2007). Targeting the Raf-MEK-ERK mitogenactivated protein kinase cascade for the treatment of cancer. Oncogene, 26(22): 3291–3310
Roca H, Varsos Z, Pienta K J (2008). CCL2 protects prostate cancer PC3 cells from autophagic death via phosphatidylinositol 3-kinase/AKTdependent survivin up-regulation. J Biol Chem, 283(36): 25057–25073
Roninson I B (2003). Tumor cell senescence in cancer treatment. Cancer Res, 63(11): 2705–2715
Samaratunga H, Fairweather P, Purdie D (2005). Significance of stromal reaction patterns in invasive urothelial carcinoma. Am J Clin Pathol, 123(6): 851–857
Sankala H M, Hait N C, Paugh S W, Shida D, Lépine S, Elmore L W, Dent P, Milstien S, Spiegel S (2007). Involvement of sphingosine kinase 2 in p53-independent induction of p21 by the chemotherapeutic drug doxorubicin. Cancer Res, 67(21): 10466–10474
Schoppmann S F, Jesch B, Riegler M F, Maroske F, Schwameis K, Jomrich G, Birner P (2013). Podoplanin expressing cancer associated fibroblasts are associated with unfavourable prognosis in adenocarcinoma of the esophagus. Clin Exp Metastasis, 30(4): 441–446
Seslar S P, Nakamura T, Byers S W (1993). Regulation of fibroblast hepatocyte growth factor/scatter factor expression by human breast carcinoma cell lines and peptide growth factors. Cancer Res, 53(6): 1233–1238
Shimao Y, Nabeshima K, Inoue T, Koono M (1999). Role of fibroblasts in HGF/SF-induced cohort migration of human colorectal carcinoma cells: fibroblasts stimulate migration associated with increased fibronectin production via upregulated TGF-beta1. Int J Cancer, 82(3): 449–458
Shinde A V, Frangogiannis N G (2013). Fibroblasts in myocardial infarction: A role in inflammation and repair. J Mol Cell Cardiol, doi: 10.1016/j.yjmcc.2013.11.015
Siegsmund M J, Kreukler C, Steidler A, Nebe T, Köhrmann K U, Alken P (1997). Multidrug resistance in androgen-independent growing rat prostate carcinoma cells is mediated by P-glycoprotein. Urol Res, 25(1): 35–41
Silzle T, Kreutz M, Dobler M A, Brockhoff G, Knuechel R, Kunz-Schughart L A (2003). Tumor-associated fibroblasts recruit blood monocytes into tumor tissue. Eur J Immunol, 33(5): 1311–1320
Smith N Z (2012). Treating metastatic breast cancer with systemic chemotherapies: current trends and future perspectives. Clin J Oncol Nurs, 16(2): E33–E43
Soon P S, Kim E, Pon C K, Gill A J, Moore K, Spillane A J, Benn D E, Baxter R C (2013). Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal transition in breast cancer cells. Endocr Relat Cancer, 20(1): 1–12
Stoker M, Gherardi E, Perryman M, Gray J (1987). Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature, 327(6119): 239–242
Stoker M, Perryman M (1985). An epithelial scatter factor released by embryo fibroblasts. J Cell Sci, 77: 209–223
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 (2012). Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature, 487(7408): 500–504
Stupack D G, Cheresh D A (2002). Get a ligand, get a life: integrins, signaling and cell survival. J Cell Sci, 115(Pt 19): 3729–3738
Sturm I, Bosanquet A G, Hermann S, Güner D, Dörken B, Daniel P T (2003). Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy. Cell Death Differ, 10(4): 477–484
Sun Y, Campisi J, Higano C, Beer T M, Porter P, Coleman I, True L, Nelson P S (2012). Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med, 18(9): 1359–1368
Takeuchi K, Ito F (2011). Receptor tyrosine kinases and targeted cancer therapeutics. Biol Pharm Bull, 34(12): 1774–1780
Taylor C W, Dalton W S, Parrish P R, Gleason M C, Bellamy W T, Thompson F H, Roe D J, Trent J M (1991). Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line. Br J Cancer, 63(6): 923–929
Tegze B, Szállási Z, Haltrich I, Pénzváltó Z, Tóth Z, Likó I, Gyorffy B (2012). Parallel evolution under chemotherapy pressure in 29 breast cancer cell lines results in dissimilar mechanisms of resistance. PLoS ONE, 7(2): e30804
Thomas D, Vadas M, Lopez A (2004). Regulation of haematopoiesis by growth factors-emerging insights and therapies. Expert Opin Biol Ther, 4(6): 869–879
Tjomsland V, Niklasson L, Sandström P, Borch K, Druid H, Bratth-ll C, Messmer D, Larsson M, Spångeus A (2011). The desmoplastic stroma plays an essential role in the accumulation and modulation of infiltrated immune cells in pancreatic adenocarcinoma. Clin Dev Immunol, 2011: 212810
Torres S, Bartolomé R A, Mendes M, Barderas R, Fernandez-AceñeroM J, Peláez-García A, Peña C, Lopez-Lucendo M, Villar-Vázquez R, de Herreros A G, Bonilla F, Casal J I (2013). Proteome profiling of cancer-associated fibroblasts identifies novel proinflammatory signatures and prognostic markers for colorectal cancer. Clin Cancer Res, 19(21): 6006–6019
Tsujino T, Seshimo I, Yamamoto H, Ngan C Y, Ezumi K, Takemasa I, Ikeda M, Sekimoto M, Matsuura N, Monden M (2007). Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clin Cancer Res, 13(7): 2082–2090
Tsuyada A, Chow A, Wu J, Somlo G, Chu P, Loera S, Luu T, Li A X, Wu X, Ye W, Chen S, Zhou W, Yu Y, Wang Y Z, Ren X, Li H, Scherle P, Kuroki Y, Wang S E (2012). CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res, 72(11): 2768–2779
Uchida D, Kawamata H, Omotehara F, Nakashiro Ki, Kimura-Yanagawa T, Hino S, Begum N M, Hoque M O, Yoshida H, Sato M, Fujimori T (2001). Role of HGF/c-met system in invasion and metastasis of oral squamous cell carcinoma cells in vitro and its clinical significance. Int J Cancer, 93(4): 489–496
van Leenders G J, Sookhlall R, TeubelW J, de Ridder C M, Reneman S, Sacchetti A, Vissers K J, van Weerden W, Jenster G (2011). Activation of c-MET induces a stem-like phenotype in human prostate cancer. PLoS ONE, 6(11): e26753
Vermeulen L, De Sousa E Melo F, van der Heijden M, Cameron K, de Jong J H, Borovski T, Tuynman J B, Todaro M, Merz C, Rodermond H, Sprick M R, Kemper K, Richel D J, Stassi G, Medema J P (2010). Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol, 12(5): 468–476
Wang B, Liu K, Lin H Y, Bellam N, Ling S, LinW C (2010). 14-3-3Tau regulates ubiquitin-independent proteasomal degradation of p21, a novel mechanism of p21 downregulation in breast cancer. Mol Cell Biol, 30(6): 1508–1527
Wang P, Nishitani M A, Tanimoto S, Kishimoto T, Fukumori T, Takahashi M, and Kanayama H O (2007). Bladder cancer cell invasion is enhanced by cross-talk with fibroblasts through hepatocyte growth factor. Urology, 69(4): 780–784
Wang Q, Fiel M I, Blank S, Luan W, Kadri H, Kim K W, Manizate F, Rosenblatt A G, Labow D M, Schwartz M E, Hiotis S P (2013). Impact of liver fibrosis on prognosis following liver resection for hepatitis B-associated hepatocellular carcinoma. Br J Cancer, 109(3): 573–581
Wang W, Li Q, Yamada T, Matsumoto K, Matsumoto I, Oda M, Watanabe G, Kayano Y, Nishioka Y, Sone S, Yano S (2009). Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Clin Cancer Res, 15(21): 6630–6638
Wartenberg M, Frey C, Diedershagen H, Ritgen J, Hescheler J, Sauer H (1998). Development of an intrinsic P-glycoprotein-mediated doxorubicin resistance in quiescent cell layers of large, multicellular prostate tumor spheroids. Int J Cancer, 75(6): 855–863
White G E, Iqbal A J, Greaves D R (2013). CC chemokine receptors and chronic inflammation-therapeutic opportunities and pharmacological challenges. Pharmacol Rev, 65(1): 47–89
Wilson K J, Mill C, Lambert S, Buchman J, Wilson T R, Hernandez-Gordillo V, Gallo R M, Ades L M, Settleman J, Riese D J 2nd (2012a). EGFR ligands exhibit functional differences in models of paracrine and autocrine signaling. Growth Factors, 30(2): 107–116
Wilson T R, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J, Ribas A, Li J, Moffat J, Sutherlin D P, Koeppen H, Merchant M, Neve R, and Settleman J (2012b). Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature, 487(7408): 505–509
Wishart G C, Bissett D, Paul J, Jodrell D, Harnett A, Habeshaw T, Kerr D J, Macham M A, Soukop M, Leonard R C, et al (1994). Quinidine as a resistance modulator of epirubicin in advanced breast cancer: mature results of a placebo-controlled randomized trial. J Clin Oncol, 12(9): 1771–1777
Wong M P, Cheung K N, Yuen S T, Fu K H, Chan A S, Leung S Y, Chung L P (1998). Monocyte chemoattractant protein-1 (MCP-1) expression in primary lymphoepithelioma-like carcinomas (LELCs) of the lung. J Pathol, 186(4): 372–377
Wu K J (2011). Direct activation of Bmi1 by Twist1: implications in cancer stemness, epithelial-mesenchymal transition, and clinical significance. Chang Gung Med J, 34(3): 229–238
Wu MH, Hong H C, Hong TM, Chiang WF, Jin Y T, Chen Y L (2011). Targeting galectin-1 in carcinoma-associated fibroblasts inhibits oral squamous cell carcinoma metastasis by downregulating MCP-1/CCL2 expression. Clin Cancer Res, 17(6): 1306–1316
Xiong J, Balcioglu H E, Danen E H (2013). Integrin signaling in control of tumor growth and progression. Int J Biochem Cell Biol, 45(5): 1012–1015
Xu D, Xu H, Ren Y, Liu C, Wang X, Zhang H, Lu P (2012). Cancer stem cell-related gene periostin: a novel prognostic marker for breast cancer. PLoS ONE, 7(10): e46670
Yamada T, Matsumoto K, Wang W, Li Q, Nishioka Y, Sekido Y, Sone S, Yano S (2010). Hepatocyte growth factor reduces susceptibility to an irreversible epidermal growth factor receptor inhibitor in EGFRT790M mutant lung cancer. Clin Cancer Res, 16(1): 174–183
Yasunaga M, Yamasaki F, Tokunaga O, Iwasaka T (2003). Endometrial carcinomas with lymph node involvement: novel histopathologic factors for predicting prognosis. Int J Gynecol Pathol, 22(4): 341–346
Yoshida S, Harada T, Iwabe T, Taniguchi F, Fujii A, Sakamoto Y, Yamauchi N, Shiota G, Terakawa N (2002). Induction of hepatocyte growth factor in stromal cells by tumor-derived basic fibroblast growth factor enhances growth and invasion of endometrial cancer. J Clin Endocrinol Metab, 87(5): 2376–2383
Yu S, Xia S, Yang D, Wang K, Yeh S, Gao Z, Chang C (2013). Androgen receptor in human prostate cancer-associated fibroblasts promotes prostate cancer epithelial cell growth and invasion. Med Oncol, 30(3): 674
Zhang J, Yang P L, Gray N S (2009). Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer, 9(1): 28–39
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Fang, W.B., Yao, M. & Cheng, N. Priming cancer cells for drug resistance: role of the fibroblast niche. Front. Biol. 9, 114–126 (2014). https://doi.org/10.1007/s11515-014-1300-8
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DOI: https://doi.org/10.1007/s11515-014-1300-8