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研究生：	黃聖芙 Huang, Sheng-Fu
論文名稱：	KRAS誘導之胰臟癌中腫瘤巨噬細胞存在之必要性 Tumor Associated Macrophage is Required for KRAS-Driven Pancreatic Tumorigenesis
指導教授：	沈延盛 Shan, Yan-Shen
學位類別：	碩士 Master
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2013
畢業學年度：	101
語文別：	英文
論文頁數：	78
中文關鍵詞：	胰臟癌、KRAS基因突變、腫瘤周圍巨噬細胞、腫瘤微環境
外文關鍵詞：	Pancreatic ductal adenocarcinoma (PDAC), KRAS, tumor associated macrophages (TAMs), Tumor microenvironment
相關次數：	點閱：118 下載：5
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胰臟癌是高度惡性腫瘤，好發於歐美與澳洲等國家，其次是台灣，胰臟癌病患的五年內存活率不到百分之五。胰臟癌非常難以被診斷出，且其具有高轉移性，導致病患在手術或化療治療後，預後不佳或是易復發的狀況，因此突破現今胰臟癌治療方式是非常重要的。先前研究證實，慢性胰臟發炎可能誘導胰臟病變、促進胰臟癌的進程。先前研究更提出，將近百分之九十五的胰臟癌病患都具有KRAS基因點突變的狀況，且KRAS對腫瘤的形成和轉移有高度相關性，但只在誘導胰臟炎的KRAS突變基因轉殖鼠中，才能成功且迅速的形成胰臟癌。在胰臟癌病患的腫瘤組織切片當中，也觀察到大量的巨噬細胞分布在腫瘤周圍，一再地顯示出胰臟癌的形成與發炎相關免疫反應之相關性。本研究將試圖釐清Kras基因異常與腫瘤周圍巨噬細胞的相關性。我們藉由Boyden camber 建立胰臟癌細胞與單核球共培養系統，爾後觀察到單核球受到癌細胞吸引，並成功分化成腫瘤周圍巨噬細胞，與胰臟癌細胞進行作用：刺激酪氨酸蛋白激酶受體活化癌細胞的Kras 蛋白，進而增強胰臟癌細胞的移動及增生，且藉由介白素八號(IL-8)增強腫瘤周圍巨噬細胞的分化及生成，刺激此路徑形成正向回饋機制。在動物模式中，成功的證實腫瘤周圍巨噬細胞受到界白素八號調控，且抑制腫瘤周圍巨噬細胞生成，可降低腫瘤生長。最後，在臨床上證實胰臟癌病患的腫瘤切片中，發現介白素八號分布在高表現KRAS的癌細胞周遭，且介白素八號與腫瘤巨噬細胞表現較高的胰臟癌病患其存活率較差。本研究證實KRAS突變的胰臟癌透過介白素八號刺激腫瘤周圍巨噬細胞產生，促進胰臟癌生長。當前胰臟癌無任何的標靶治療或有效藥物可以使用，此研究也對臨床治療提出新方向，在治療胰臟癌的同時也將腫瘤周圍巨噬細胞納入治療範圍，藉由介白素八號短肽作為化學治療的佐劑，進而有效的治療胰臟癌。

Pancreatic cancer is the most lethal human malignancies due to its insidious onset and drug resistance. The most common form of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). The average survival rate of PDAC is less than 6 months, and it often experiences local or metastasis recurrence even if treated with surgery. Mutations in KRAS are found in more than 95% PDAC patients; most of them are G12D or G12V point mutations, which are confirmed to promote pancreatic cancer progression. In the previous studies, pancreatitis is necessary for pancreatic cancer initiation, and tumor-associated macrophages (TAMs) might play an important role in tumor progression. We suggested that TAMs promote pancreatic cancer progression through up-regulation of KRAS activity. As the result, high stage up-regulates the Epithelial-Mesenchymal transition level and down-regulates cell stiffness. In addition, cell stiffness is mediated by KRAS. After pancreatic cancer cells stimulate to monocytes, they promote the monocytes differentiation into TAMs. TAMs up-regulate KRAS activation and epithelial-mesenchymal transition via MAPK signaling pathway; moreover, it also enhances cancer cell proliferation and migration. KRAS activation also drives monocytes differentiating into TAMs by IL-8. At last, we demonstrated that the expression of IL-8 not only correlates with the stage of pancreatic cancer, but also links to the poor survival rates. In animal models, tumor volume decreases significantly after the combination therapy of GdCl3 (TAM inhibitor) or IL-8 peptide with Gemcitabine. Those results suggest that KRAS promotes tumorigenesis through IL-8 secretion, which mediated TAMs formation and subsequently advanced the tumor progression. In this study, we provide a new therapeutic avenue for PDAC due to the inhibition of IL-8 stimulation and suppression in TAM formation.

Contents
摘要	I
Abstract	III
Acknowledgements	V
Contents	VII
I.	Abbreviation	XI
II.	Introduction	1
1	Pancreatic cancer	1
1.1	Pancreatic cancer	1
1.2	KRAS mutation	2
2	Pancreatitis	3
2.1	Pancreatitis	3
3	Tumor microenvironment	4
3.1	Tumor microenvironment in PDAC	4
3.2	Inflammatory cells in tumor microenvironment	5
3.3	Tumor associated macrophage	6
4	Research motive	7
4.1	Significance	7
4.2	Specific aims	7
III.	Material and methods	8
Cell culture	8
Transformation	8
Plasmid isolation	9
Tetracycline-inducible stable cell line	10
Treatment of IL-8 recombined protein and IL-8 peptide	10
RNA interference	11
Co-culture system	11
Protein extraction	12
KRAS activation assay	12
Western Blotting (WB)	13
RNA extraction	13
Reverse transcriptase-polymerase chain reaction (RT-PCR)	14
Real-time polymerase chain reaction	15
Cell stiffness	15
Migration assay	16
Invasion assay	16
Cytokine array	17
Phagocytosis assay	18
Tumor formation in NOD/SCID mice and combination therapy	18
Immunohistochemistry (IHC) and immunofluorescence (IF)	19
Flow cytometric analyses	20
Statistical analysis	20
IV.	Results	21
KRAS is highly expressed in pancreatic cancer patients	21
KRAS mediate the epithelial-mesenchymal transition, stiffness and mobility of pancreatic cancer cells.	21
High expression of Tumor-associated macrophage (TAM) leads to poor prognosis in pancreatic cancer.	22
TAMs are increased after co-cultured with pancreatic cancer.	22
TAMs accelerate the activation of KRAS in pancreatic cancer.	23
TAMs turn on the MAPK pathway via accelerating KRAS activity	24
TAM promotes epithelial-mesenchymal transition, cell mobility and proliferation by KRAS activation.	25
KRAS promotes tumor progression by accelerating tumor-associated macrophage (TAM) formation.	25
Pancreatic cancers cells secret IL-8, and promote TAM formation.	26
Up-regulation of IL-8 and CD204 in pancreatic cancer patients correlates with poor progression	27
Inhibiting IL-8 to decrease the epithelial-mesenchymal transition in pancreatic cancer	28
The inhibition of TAM formation slows the pancreatic tumor growth in NOD-SCID mice	29
IL-8 peptide inhibits TAM formation and slows the pancreatic tumor growth in NOD-SCID mice	29
V.	Discussion	31
Oncogenic KRAS is necessary for pancreatic carcinogenesis.	31
TAM stimulates EGFR and up-regulates KRAS activity to promote the initiation of pancreatic carcinogenesis	32
Immunotherapy for pancreatic cancer: IL-8 peptide suppresses TAM formation and subsequently slows the tumor growth.	33
Microenvironment suppresses the immune system and promotes the progression of pancreatic cancer	34
VI.	Reference	36
VII.	Figures	42
Figure 1	.Clinical evidence indicated that KRAS is high expression in pancreatic cancer patients.	42
Figure 2	. The epithelial-mesenchymal transition level and stiffness in pancreatic cancer cell lines.	43
Figure 3	. KRAS mediate the cell stiffness and mobility in pancreatic cancer cells.	44
Figure 4	. Clinical evidence indicated that high expression of TAM lead poor outcome in pancreatic cancer patients	47
Figure 5	. Co-culture system mimics the interaction between pancreatic cancer cells and monocytes.	47
Figure 6	. Tumor-associated macrophage (TAM) up-regulates KRAS activity.	49
Figure 7	. Tumor-associated macrophage (TAM) up-regulates KRAS activity to up-regulate EGFR downstream signaling pathway	50
Figure 8	. TAM promotes epithelial-mesenchymal transition by KRAS activation.	51
Figure 9	. TAM enhances cell mobility and proliferation by KRAS activation.	52
Figure 10	. KRAS promotes tumor progression by accelerating tumor-associated macrophage (TAM) formation	55
Figure 11	. Pancreatic cancer secret IL-8, and promote TAM formation	59
Figure 12	. Up-regulation of IL-8 and CD204 in pancreatic cancer patients correlates with poor progression	61
Figure 13	. Inhibiting IL-8 to decrease the epithelial-mesenchymal transition in pancreatic cancer	64
Figure 14	. The inhibition of TAM formation slows the pancreatic tumor growth in NOD-SCID mice	67
Figure 15	. IL-8 peptide inhibits TAM formation and slows the pancreatic tumor growth in NOD-SCID mice	70
VIII.	Tables	71
Table 1.	Grade for KRAS expression in PDAC patient.	71
Table 2.	Schema presents a co-culture system that provides an in vitro microenvironment to mimic infiltration of TAM in pancreatic cancer cell.	72
IX.	Appendix	73
Appendix 1. List of antibody	73
Appendix 2. List of primer	75
X.	Curriculum vitae	78

                                    

(2010). "StatBite. U.S. pancreatic cancer rates." J Natl Cancer Inst 102(24): 1822.
Aggarwal, B. B., S. Shishodia, S. K. Sandur, M. K. Pandey and G. Sethi (2006). "Inflammation and cancer: how hot is the link?" Biochem Pharmacol 72(11): 1605-1621.
Ardito, C. M., B. M. Gruner, K. K. Takeuchi, C. Lubeseder-Martellato, N. Teichmann, P. K. Mazur, K. E. Delgiorno, E. S. Carpenter, C. J. Halbrook, J. C. Hall, D. Pal, T. Briel, A. Herner, M. Trajkovic-Arsic, B. Sipos, G. Y. Liou, P. Storz, N. R. Murray, D. W. Threadgill, M. Sibilia, M. K. Washington, C. L. Wilson, R. M. Schmid, E. W. Raines, H. C. Crawford and J. T. Siveke (2012). "EGF receptor is required for KRAS-induced pancreatic tumorigenesis." Cancer Cell 22(3): 304-317.
Baines, A. T., D. Xu and C. J. Der (2011). "Inhibition of Ras for cancer treatment: the search continues." Future Med Chem 3(14): 1787-1808.
Balkwill, F. and A. Mantovani (2001). "Inflammation and cancer: back to Virchow?" Lancet 357(9255): 539-545.
Bansal, P. and A. Sonnenberg (1995). "Pancreatitis is a risk factor for pancreatic cancer." Gastroenterology 109(1): 247-251.
Browning, M. J. and W. F. Bodmer (1992). "MHC antigens and cancer: implications for T-cell surveillance." Curr Opin Immunol 4(5): 613-618.
Chen, H., H. Tu, Z. Q. Meng, Z. Chen, P. Wang and L. M. Liu (2010). "K-ras mutational status predicts poor prognosis in unresectable pancreatic cancer." Eur J Surg Oncol 36(7): 657-662.
Chew, V., H. C. Toh and J. P. Abastado (2012). "Immune microenvironment in tumor progression: characteristics and challenges for therapy." J Oncol 2012: 608406.
Collins, M. A., F. Bednar, Y. Zhang, J. C. Brisset, S. Galban, C. J. Galban, S. Rakshit, K. S. Flannagan, N. V. Adsay and M. Pasca di Magliano (2012). "Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice." J Clin Invest 122(2): 639-653.
Collisson, E. A., A. Sadanandam, P. Olson, W. J. Gibb, M. Truitt, S. Gu, J. Cooc, J. Weinkle, G. E. Kim, L. Jakkula, H. S. Feiler, A. H. Ko, A. B. Olshen, K. L. Danenberg, M. A. Tempero, P. T. Spellman, D. Hanahan and J. W. Gray (2011). "Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy." Nat Med 17(4): 500-503.
Cross, S. E., Y. S. Jin, J. Rao and J. K. Gimzewski (2007). "Nanomechanical analysis of cells from cancer patients." Nat Nanotechnol 2(12): 780-783.
Cui, J., W. Jiang, S. Wang, L. Wang and K. Xie (2012). "Role of Wnt/beta-catenin signaling in drug resistance of pancreatic cancer." Curr Pharm Des 18(17): 2464-2471.
De Monte, L., M. Reni, E. Tassi, D. Clavenna, I. Papa, H. Recalde, M. Braga, V. Di Carlo, C. Doglioni and M. P. Protti (2011). "Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer." J Exp Med 208(3): 469-478.
Deramaudt, T. and A. K. Rustgi (2005). "Mutant KRAS in the initiation of pancreatic cancer." Biochim Biophys Acta 1756(2): 97-101.
Erkan, M., C. Reiser-Erkan, C. W. Michalski and J. Kleeff (2010). "Tumor microenvironment and progression of pancreatic cancer." Exp Oncol 32(3): 128-131.
Farrow, B., D. Albo and D. H. Berger (2008). "The role of the tumor microenvironment in the progression of pancreatic cancer." J Surg Res 149(2): 319-328.
Ferrone, C. R., R. Pieretti-Vanmarcke, J. P. Bloom, H. Zheng, J. Szymonifka, J. A. Wargo, S. P. Thayer, G. Y. Lauwers, V. Deshpande, M. Mino-Kenudson, C. Fernandez-del Castillo, K. D. Lillemoe and A. L. Warshaw (2012). "Pancreatic ductal adenocarcinoma: long-term survival does not equal cure." Surgery 152(3 Suppl 1): S43-49.
Friday, B. B. and A. A. Adjei (2005). "K-ras as a target for cancer therapy." Biochim Biophys Acta 1756(2): 127-144.
Fujisawa, N., Y. Sakao, S. Hayashi, W. A. Hadden, 3rd, C. L. Harmon and E. J. Miller (2000). "alpha-Chemokine growth factors for adenocarcinomas; a synthetic peptide inhibitor for alpha-chemokines inhibits the growth of adenocarcinoma cell lines." J Cancer Res Clin Oncol 126(1): 19-26.
Hao, K., X. D. Tian, C. F. Qin, X. H. Xie and Y. M. Yang (2013). "Hedgehog signaling pathway regulates human pancreatic cancer cell proliferation and metastasis." Oncol Rep 29(3): 1124-1132.
Heinemann, V., S. Boeck, A. Hinke, R. Labianca and C. Louvet (2008). "Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer." BMC Cancer 8: 82.
Hingorani, S. R., E. F. Petricoin, A. Maitra, V. Rajapakse, C. King, M. A. Jacobetz, S. Ross, T. P. Conrads, T. D. Veenstra, B. A. Hitt, Y. Kawaguchi, D. Johann, L. A. Liotta, H. C. Crawford, M. E. Putt, T. Jacks, C. V. Wright, R. H. Hruban, A. M. Lowy and D. A. Tuveson (2003). "Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse." Cancer Cell 4(6): 437-450.
Hingorani, S. R., L. Wang, A. S. Multani, C. Combs, T. B. Deramaudt, R. H. Hruban, A. K. Rustgi, S. Chang and D. A. Tuveson (2005). "Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice." Cancer Cell 7(5): 469-483.
Hoh, J. H. and C. A. Schoenenberger (1994). "Surface morphology and mechanical properties of MDCK monolayers by atomic force microscopy." J Cell Sci 107 ( Pt 5): 1105-1114.
Huguet, F., N. Girard, C. S. Guerche, C. Hennequin, F. Mornex and D. Azria (2009). "Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review." J Clin Oncol 27(13): 2269-2277.
Hui, C. C. and S. Angers (2011). "Gli proteins in development and disease." Annu Rev Cell Dev Biol 27: 513-537.
Hwang, R. F., T. Moore, T. Arumugam, V. Ramachandran, K. D. Amos, A. Rivera, B. Ji, D. B. Evans and C. D. Logsdon (2008). "Cancer-associated stromal fibroblasts promote pancreatic tumor progression." Cancer Res 68(3): 918-926.
Izeradjene, K., C. Combs, M. Best, A. Gopinathan, A. Wagner, W. M. Grady, C. X. Deng, R. H. Hruban, N. V. Adsay, D. A. Tuveson and S. R. Hingorani (2007). "Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas." Cancer Cell 11(3): 229-243.
Jancik, S., J. Drabek, D. Radzioch and M. Hajduch (2010). "Clinical relevance of KRAS in human cancers." J Biomed Biotechnol 2010: 150960.
Jeffrey, R. B. (2012). "Pancreatic cancer: radiologic imaging." Gastroenterol Clin North Am 41(1): 159-177.
Joyce, J. A. and J. W. Pollard (2009). "Microenvironmental regulation of metastasis." Nat Rev Cancer 9(4): 239-252.
Jurcic, Z., V. Oberiter and D. Rudar (1981). "Gallstone associated with acute pancreatitis in a child." Helv Paediatr Acta 36(3): 255-261.
Kimura, Y., S. Arata, T. Takada, K. Hirata, M. Yoshida, T. Mayumi, M. Hirota, K. Takeda, T. Gabata, H. Amano, K. Wada, M. Sekimoto, M. Yokoe, S. Kiriyama and T. Ito (2010). "Gallstone-induced acute pancreatitis." J Hepatobiliary Pancreat Sci 17(1): 60-69.
Kindler, H. L., K. Wroblewski, J. A. Wallace, M. J. Hall, G. Locker, S. Nattam, E. Agamah, W. M. Stadler and E. E. Vokes (2012). "Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium." Invest New Drugs 30(1): 382-386.
Koido, S., S. Homma, A. Takahara, Y. Namiki, S. Tsukinaga, J. Mitobe, S. Odahara, T. Yukawa, H. Matsudaira, K. Nagatsuma, K. Uchiyama, K. Satoh, M. Ito, H. Komita, H. Arakawa, T. Ohkusa, J. Gong and H. Tajiri (2011). "Current immunotherapeutic approaches in pancreatic cancer." Clin Dev Immunol 2011: 267539.
Korc, M. (2007). "Pancreatic cancer-associated stroma production." Am J Surg 194(4 Suppl): S84-86.
Kullmann, F., A. Hartmann, R. Stohr, H. Messmann, M. M. Dollinger, J. Trojan, M. Fuchs, S. Hollerbach, J. Harder, M. Troppmann, A. Kutscheidt and E. Endlicher (2011). "KRAS mutation in metastatic pancreatic ductal adenocarcinoma: results of a multicenter phase II study evaluating efficacy of cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line therapy." Oncology 81(1): 3-8.
Lee, J., K. T. Jang, C. S. Ki, T. Lim, Y. S. Park, H. Y. Lim, D. W. Choi, W. K. Kang, K. Park and J. O. Park (2007). "Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma." Cancer 109(8): 1561-1569.
Liao, W. T., H. S. Yu, J. L. Arbiser, C. H. Hong, B. Govindarajan, C. Y. Chai, W. J. Shan, Y. F. Lin, G. S. Chen and C. H. Lee (2010). "Enhanced MCP-1 release by keloid CD14+ cells augments fibroblast proliferation: role of MCP-1 and Akt pathway in keloids." Exp Dermatol 19(8): e142-150.
Long, J., Y. Zhang, X. Yu, J. Yang, D. G. LeBrun, C. Chen, Q. Yao and M. Li (2011). "Overcoming drug resistance in pancreatic cancer." Expert Opin Ther Targets 15(7): 817-828.
Lowenfels, A. B., P. Maisonneuve, G. Cavallini, R. W. Ammann, P. G. Lankisch, J. R. Andersen, E. P. Dimagno, A. Andren-Sandberg and L. Domellof (1993). "Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group." N Engl J Med 328(20): 1433-1437.
Malka, D., P. Hammel, F. Maire, P. Rufat, I. Madeira, F. Pessione, P. Levy and P. Ruszniewski (2002). "Risk of pancreatic adenocarcinoma in chronic pancreatitis." Gut 51(6): 849-852.
Malumbres, M. and M. Barbacid (2003). "RAS oncogenes: the first 30 years." Nat Rev Cancer 3(6): 459-465.
Mantovani, A., S. Sozzani, M. Locati, P. Allavena and A. Sica (2002). "Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes." Trends Immunol 23(11): 549-555.
Matsuno, S., S. Egawa, S. Fukuyama, F. Motoi, M. Sunamura, S. Isaji, T. Imaizumi, S. Okada, H. Kato, K. Suda, A. Nakao, T. Hiraoka, R. Hosotani and K. Takeda (2004). "Pancreatic Cancer Registry in Japan: 20 years of experience." Pancreas 28(3): 219-230.
McCarthy, N. (2011). "Tumour microenvironment: target practice." Nat Rev Cancer 11(5): 315.
Mohla, S. (2007). "Tumor microenvironment." J Cell Biochem 101(4): 801-804.
Moore, M. J., D. Goldstein, J. Hamm, A. Figer, J. R. Hecht, S. Gallinger, H. J. Au, P. Murawa, D. Walde, R. A. Wolff, D. Campos, R. Lim, K. Ding, G. Clark, T. Voskoglou-Nomikos, M. Ptasynski and W. Parulekar (2007). "Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group." J Clin Oncol 25(15): 1960-1966.
Morris, J. P. t., S. C. Wang and M. Hebrok (2010). "KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma." Nat Rev Cancer 10(10): 683-695.
Navas, C., I. Hernandez-Porras, A. J. Schuhmacher, M. Sibilia, C. Guerra and M. Barbacid (2012). "EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma." Cancer Cell 22(3): 318-330.
Neesse, A., P. Michl, K. K. Frese, C. Feig, N. Cook, M. A. Jacobetz, M. P. Lolkema, M. Buchholz, K. P. Olive, T. M. Gress and D. A. Tuveson (2011). "Stromal biology and therapy in pancreatic cancer." Gut 60(6): 861-868.
Robinson, B. D., G. L. Sica, Y. F. Liu, T. E. Rohan, F. B. Gertler, J. S. Condeelis and J. G. Jones (2009). "Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination." Clin Cancer Res 15(7): 2433-2441.
Rowell, C. A., J. J. Kowalczyk, M. D. Lewis and A. M. Garcia (1997). "Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo." J Biol Chem 272(22): 14093-14097.
Sarles, H. (1972). "Alcohol and chronic pancreatitis." Proc R Soc Med 65(10): 847-849.
Sica, A., T. Schioppa, A. Mantovani and P. Allavena (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.
Siegel, R., D. Naishadham and A. Jemal (2012). "Cancer statistics, 2012." CA Cancer J Clin 62(1): 10-29.
Simone, R. E., M. Russo, A. Catalano, G. Monego, K. Froehlich, V. Boehm and P. Palozza (2011). "Lycopene inhibits NF-kB-mediated IL-8 expression and changes redox and PPARgamma signalling in cigarette smoke-stimulated macrophages." PLoS One 6(5): e19652.
Singh, A., P. Greninger, D. Rhodes, L. Koopman, S. Violette, N. Bardeesy and J. Settleman (2009). "A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival." Cancer Cell 15(6): 489-500.
Solinas, G., G. Germano, A. Mantovani and P. Allavena (2009). "Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation." J Leukoc Biol 86(5): 1065-1073.
Stegmaier, J. C., C. Kirchhoff, V. Bogner, M. Matz, K. G. Kanz, W. Mutschler and P. Biberthaler (2008). "Dynamics of neutrophilic NF-kB translocation in relation to IL-8 mRNA expression after major trauma." Inflamm Res 57(11): 547-554.
Strieter, R. M., R. Wiggins, S. H. Phan, B. L. Wharram, H. J. Showell, D. G. Remick, S. W. Chensue and S. L. Kunkel (1989). "Monocyte chemotactic protein gene expression by cytokine-treated human fibroblasts and endothelial cells." Biochem Biophys Res Commun 162(2): 694-700.
Swartz, M. A., N. Iida, E. W. Roberts, S. Sangaletti, M. H. Wong, F. E. Yull, L. M. Coussens and Y. A. DeClerck (2012). "Tumor microenvironment complexity: emerging roles in cancer therapy." Cancer Res 72(10): 2473-2480.
Takamori, H., Z. G. Oades, O. C. Hoch, M. Burger and I. U. Schraufstatter (2000). "Autocrine growth effect of IL-8 and GROalpha on a human pancreatic cancer cell line, Capan-1." Pancreas 21(1): 52-56.
Tan, M. C., P. S. Goedegebuure, B. A. Belt, B. Flaherty, N. Sankpal, W. E. Gillanders, T. J. Eberlein, C. S. Hsieh and D. C. Linehan (2009). "Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer." J Immunol 182(3): 1746-1755.
Thayer, S. P., M. P. di Magliano, P. W. Heiser, C. M. Nielsen, D. J. Roberts, G. Y. Lauwers, Y. P. Qi, S. Gysin, C. Fernandez-del Castillo, V. Yajnik, B. Antoniu, M. McMahon, A. L. Warshaw and M. Hebrok (2003). "Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis." Nature 425(6960): 851-856.
Tseng, C. H. (2013). "Diabetes, insulin use, smoking, and pancreatic cancer mortality in Taiwan." Acta Diabetol.
Ueda, J., M. Tanaka, T. Ohtsuka, S. Tokunaga, T. Shimosegawa and R. C. I. D. Pancreas (2013). "Surgery for chronic pancreatitis decreases the risk for pancreatic cancer: A multicenter retrospective analysis." Surgery 153(3): 357-364.
Uomo, G. and G. Manes (2007). "Risk factors of chronic pancreatitis." Dig Dis 25(3): 282-284.
Villalta, S. A., H. X. Nguyen, B. Deng, T. Gotoh and J. G. Tidball (2009). "Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy." Hum Mol Genet 18(3): 482-496.
Vonlaufen, A., S. Joshi, C. Qu, P. A. Phillips, Z. Xu, N. R. Parker, C. S. Toi, R. C. Pirola, J. S. Wilson, D. Goldstein and M. V. Apte (2008). "Pancreatic stellate cells: partners in crime with pancreatic cancer cells." Cancer Res 68(7): 2085-2093.
Whiteside, T. L. (2008). "The tumor microenvironment and its role in promoting tumor growth." Oncogene 27(45): 5904-5912.
Whyte, D. B., P. Kirschmeier, T. N. Hockenberry, I. Nunez-Oliva, L. James, J. J. Catino, W. R. Bishop and J. K. Pai (1997). "K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors." J Biol Chem 272(22): 14459-14464.
Zhang, B., G. Yao, Y. Zhang, J. Gao, B. Yang and Z. Rao (2011). "M2-polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymphangiogenesis in lung adenocarcinoma." Clinics (Sao Paulo) 66(11): 1879-1886.

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