研究背景: Chitinase-3-like 1 (CHI3L1, 類幾丁質3) 是一種促進腫瘤生長的分泌型蛋白，可以由巨噬細胞、纖維母細胞、癌細胞等多種細胞分泌。已有研究報告指出，CHI3L1與許多發炎性疾病和癌症有關。目前大多數的研究表明，CHI3L1與肺部和肝臟纖維化有關，值得注意的是，在胰臟癌中也常見到嚴重的纖維化情況；然而，關於 CHI3L1在胰臟癌中調節纖維化的詳細機制仍然是未知的。
研究目的: 本研究旨在評估CHI3L1引起胰臟癌纖維化的潛在機制，並驗證CHI3L1是否能促進前驅細胞分化為癌症纖維母細胞 (CAF)。另外，本論文在胰臟癌為主的小鼠模型中驗證人類CHI3L1中和性單株抗體 (CHI3L1 nAb) 的抗腫瘤和抗纖維化效果。
研究結果: 免疫螢光染色結果顯示，在帶有KPPC-luc胰臟癌腫瘤的免疫正常小鼠的腫瘤組織中，CHI3L1和纖維化標記物α-SMA有共定位現象。生物資訊學方法也識別出在美國癌症基因體資料庫 (TCGA) 的胰臟癌數據中CHI3L1和CAF相關基因如ACTA2（α-SMA 的編碼基因）以及的COL1A1之間在mRNA水平有著正相關性。此外，我們驗證了重組CHI3L1蛋白促進正常纖維母細胞中α-SMA的蛋白質和mRNA表現量，表明CHI3L1可以促進CAF的形成。此外，我們還建立了癌細胞和免疫細胞共培養系統以模擬腫瘤免疫微環境，再將此共培養系統含有大量CHI3L1的上清液收集，處理於巨噬細胞（macrophage）和胰臟星狀細胞（pancreatic stellate cell, PSC）。含CHI3L1的上清液透過巨噬細胞的轉分化（transdifferentiation）和PSC激活提升了CAF相關基因的mRNA表現。另一方面，我們檢查了所開發的CHI3L1 nAb的功效，該CHI3L1 nAb成功消除了CHI3L1引起的致癌效應。在CHI3L1 nAb治療後，胰臟癌、大腸直腸癌原位小鼠模型和肺癌皮下人源化小鼠模型的血漿中CHI3L1濃度降低，腫瘤大小也相應下降。在活體內CHI3L1 nAb使胰臟癌對吉西他濱 (gemcitabine) 的治療更加敏感，並有著不亞於貝伐珠單株抗體 (bevacizumab) 的治療結果。更重要的是，CHI3L1 nAb具有顯著的抗纖維化能力，並可以重新調整免疫細胞成為抗腫瘤的型態。
研究結論: 本研究發現了CHI3L1促進胰臟癌纖維化的作用機制。此外，我們新開發的CHI3L1 nAb減少了纖維化的發生，進而限制了胰臟癌、大腸直腸癌和肺癌的腫瘤生長。

Background: Chitinase-3-like 1 (CHI3L1) is a pro-tumoral secretion protein which can be secreted by macrophages, fibroblasts, cancer cells and others. CHI3L1 has been reported to associate with many inflammatory diseases and cancers. Currently, most studies indicated that CHI3L1 correlates with lung and liver fibrosis. Notably, severe fibrosis is also commonly seen in pancreatic cancer. However, the detailed mechanism of CHI3L1-mediated fibrosis in pancreatic cancer is still unclear.
Purpose: We aim to evaluate the underlying mechanism of CHI3L1-induced fibrosis in pancreatic cancer. In addition, we verify whether CHI3L1 could promote differentiation of precursor cells into cancer associated fibroblasts (CAF). Furthermore, the anti-tumor and anti-fibrosis effects of our human neutralizing-CHI3L1 monoclonal antibody (CHI3L1 nAb) are verified in pancreatic cancer mice models.
Results: Immunofluorescence data demonstrated that CHI3L1 and fibrosis marker, smooth muscle alpha actin (α-SMA), co-localized in tumor section of KPPC-luc pancreatic cancer tumor bearing mice. Bioinformatics approaches identified the positive correlation between CHI3L1 and CAF related genes, such as ACTA2 (the gene codes for α-SMA) as well as COL1A1 at the mRNA level in pancreatic cancer dataset of TCGA. Therefore, we verified the protein and mRNA expression of fibrosis marker in recombinant CHI3L1 (rCHI3L1) treated normal fibroblasts. The data showed that mRNA and protein expression levels of α-SMA were up-regulated by rCHI3L1, indicating that CHI3L1 could promote CAF formation. Furthermore, we established cancer and immune cells co-cultured system to mimic tumor microenvironment (TME) and subsequently, collected the supernatant containing abundant CHI3L1 to treat macrophages and pancreatic stellate cells (PSCs). Of note, the mRNA levels of CAF related genes were enhanced in macrophages and PSC through macrophage trans-differentiation and PSC activation. On the other hand, we examined the functionality of our CHI3L1 nAb which successfully abrogated the oncogenic effects induced by CHI3L1 in vivo. The decreased CHI3L1 level in plasma was accompanied with smaller tumor size after CHI3L1 nAb treatment in orthotopic pancreatic tumor and colorectal cancer mice model as well as subcutaneous pancreatic and lung cancer models of humanized mice. The CHI3L1 nAb sensitized the pancreatic cancer to the gemcitabine treatment and showed comparable results as bevacizumab in colorectal cancer model in vivo. Importantly, the CHI3L1 nAb significantly exerted an anti-fibrosis effect and reprogrammed the immune cells to anti-tumor profiling.
Conclusion: This study discovers the roles of CHI3L1 in promoting fibrosis of pancreatic cancer. Moreover, our newly developed CHI3L1 nAb reduces fibrosis and therefore restricts tumor growth of pancreatic, colorectal and lung cancers.

Aoudjit F, Vuori K. Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells. Oncogene. 2001;20(36):4995-5004.
Arina A, Idel C, Hyjek EM, Alegre ML, Wang Y, Bindokas VP, Weichselbaum RR, Schreiber H. Tumor-associated fibroblasts predominantly come from local and not circulating precursors. Proc Natl Acad Sci U S A. 2016;113(27):7551-6.
Bagati A, Kumar S, Jiang P, Pyrdol J, Zou AE, Godicelj A, Mathewson ND, Cartwright ANR, Cejas P, Brown M, Giobbie-Hurder A, Dillon D, Agudo J, Mittendorf EA, Liu XS, Wucherpfennig KW. Integrin αvβ6-TGFβ-SOX4 pathway drives immune evasion in triple-negative breast cancer. Cancer Cell. 2021;39(1):54-67.e9.
Bara I, Ozier A, Girodet PO, Carvalho G, Cattiaux J, Begueret H, Thumerel M, Ousova O, Kolbeck R, Coyle AJ, Woods J, Tunon de Lara JM, Marthan R, Berger P. Role of YKL-40 in bronchial smooth muscle remodeling in asthma. Am J Respir Crit Care Med. 2012;185(7):715-22.
Barderas R, Bartolomé RA, Fernandez-Aceñero MJ, Torres S, Casal JI. High expression of IL-13 receptor α2 in colorectal cancer is associated with invasion, liver metastasis, and poor prognosis. Cancer Res. 2012;72(11):2780-90.
Barzaman K, Samadi M, Moradi-Kalbolandi S, Majidzadeh-A K, Salehi M, Jalili N, Jazayeri MH, Khorammi S, Darvishi B, Siavashi V, Shekarabi M, Farahmand L. Development of a recombinant anti-VEGFR2-EPCAM bispecific antibody to improve antiangiogenic efficiency. Exp Cell Res. 2021;405(2):112685.
Bigg HF, Wait R, Rowan AD, Cawston TE. The mammalian chitinase-like lectin, YKL-40, binds specifically to type I collagen and modulates the rate of type I collagen fibril formation. J Biol Chem. 2006;281(30):21082-21095.
Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA. 2021;325(7):669-685.
Buscail L, Bournet B, Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2020;17(3):153-168.
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298-307.
Chaves-Pérez A, Mack B, Maetzel D, Kremling H, Eggert C, Harréus U, Gires O. EpCAM regulates cell cycle progression via control of cyclin D1 expression. Oncogene. 2013;32(5):641-50.
Chen CC, Llado V, Eurich K, Tran HT, Mizoguchi E. Carbohydrate-binding motif in chitinase 3-like 1 (CHI3L1/YKL-40) specifically activates Akt signaling pathway in colonic epithelial cells. Clin Immunol. 2011;140(3):268-75.
Chen X, Zeh HJ, Kang R, Kroemer G, Tang D. Cell death in pancreatic cancer: from pathogenesis to therapy. Nat Rev Gastroenterol Hepatol. 2021;18(11):804-823.
Choi YS, Kim MJ, Choi EA, Kim S, Lee EJ, Park MJ, Kim MJ, Kim YW, Ahn HS, Jung JY, Jang G, Kim Y, Kim H, Kim K, Kim JY, Hong SM, Kim SC, Chang S. Antibody-mediated blockade for galectin-3 binding protein in tumor secretome abrogates PDAC metastasis. Proc Natl Acad Sci U S A. 2022;119(30): e2119048119.
Christofides A, Strauss L, Yeo A, Cao C, Charest A, Boussiotis VA. The complex role of tumor-infiltrating macrophages. Nat Immunol. 2022;23(8):1148-1156.
ClinicalTrials.gov https://www.clinicaltrials.gov/
Cohen N, Shani O, Raz Y, Sharon Y, Hoffman D, Abramovitz L, Erez N. Fibroblasts drive an immunosuppressive and growth-promoting microenvironment in breast cancer via secretion of chitinase 3-like 1. Oncogene. 2017;36(31):4457-4468.
Connor JR, Dodds RA, Emery JG, Kirkpatrick RB, Rosenberg M, Gowen M. Human cartilage glycoprotein 39 (HC gp-39) mRNA expression in adult and fetal chondrocytes, osteoblasts and osteocytes by in-situ hybridization. Osteoarthritis Cartilage. 2000;8(2):87-95.
Courter DL, Lomas L, Scatena M, Giachelli CM. Src kinase activity is required for integrin alphaVbeta3-mediated activation of nuclear factor-kappaB. J Biol Chem. 2005;280(13):12145-51.
Craig-Schapiro R, Perrin RJ, Roe CM, Xiong C, Carter D, Cairns NJ, Mintun MA, Peskind ER, Li G, Galasko DR, Clark CM, Quinn JF, D'Angelo G, Malone JP, Townsend RR, Morris JC, Fagan AM, Holtzman DM. YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer's disease. Biol Psychiatry. 2010;68(10):903-12.
Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, Jonker D, Osborne S, Andre N, Waterkamp D, Saunders MP; AVEX study investigators. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14(11):1077-1085.
Dahlén E, Veitonmäki N, Norlén P. Bispecific antibodies in cancer immunotherapy. Ther Adv Vaccines Immunother. 2018;6(1):3-17.
David CJ, Huang YH, Chen M, Su J, Zou Y, Bardeesy N, Iacobuzio-Donahue CA, Massagué J. TGF-β tumor suppression through a lethal EMT. Cell. 2016;164(5):1015-30.
DeLisser H, Liu Y, Desprez PY, Thor A, Briasouli P, Handumrongkul C, Wilfong J, Yount G, Nosrati M, Fong S, Shtivelman E, Fehrenbach M, Cao G, Moore DH, Nayak S, Liggitt D, Kashani-Sabet M, Debs R. Vascular endothelial platelet endothelial cell adhesion molecule 1 (PECAM-1) regulates advanced metastatic progression. Proc Natl Acad Sci U S A. 2010;107(43):18616-21.
Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10(1):9-22.
Diamantis N, Banerji U. Antibody-drug conjugates--an emerging class of cancer treatment. Br J Cancer. 2016;114(4):362-7.
Dienstmann R, Connor K, Byrne AT; COLOSSUS Consortium. Precision therapy in RAS mutant colorectal cancer. Gastroenterology. 2020;158(4):806-811.
Dixit A, Sarver A, Zettervall J, Huang H, Zheng K, Brekken RA, Provenzano PP. Targeting TNF-α-producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling. JCI Insight. 2022;7(22): e153242.
Dou C, Liu Z, Tu K, Zhang H, Chen C, Yaqoob U, Wang Y, Wen J, van Deursen J, Sicard D, Tschumperlin D, Zou H, Huang WC, Urrutia R, Shah VH, Kang N. P300 Acetyltransferase mediates stiffness-induced activation of hepatic stellate cells into tumor-promoting myofibroblasts. Gastroenterology. 2018;154(8):2209-2221.e14.
Elyada E, Bolisetty M, Laise P, Flynn WF, Courtois ET, Burkhart RA, Teinor JA, Belleau P, Biffi G, Lucito MS, Sivajothi S, Armstrong TD, Engle DD, Yu KH, Hao Y, Wolfgang CL, Park Y, Preall J, Jaffee EM, Califano A, Robson P, Tuveson DA. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 2019;9(8):1102-1123.
Fabregas JC, Ramnaraign B, George TJ. Clinical updates for colon cancer care in 2022. Clin Colorectal Cancer. 2022;21(3):198-203.
Faibish M, Francescone R, Bentley B, Yan W, Shao R. A YKL-40-neutralizing antibody blocks tumor angiogenesis and progression: a potential therapeutic agent in cancers. Mol Cancer Ther. 2011;10(5):742-51.
Francescone RA, Scully S, Faibish M, Taylor SL, Oh D, Moral L, Yan W, Bentley B, Shao R. Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma. J Biol Chem. 2011;286(17):15332-43.
Geng B, Pan J, Zhao T, Ji J, Zhang C, Che Y, Yang J, Shi H, Li J, Zhou H, Mu X, Xu C, Wang C, Xu Y, Liu Z, Wen H, You Q. Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through β-catenin/Erk/Akt signaling in gastric cancer. J Exp Clin Cancer Res. 2018;37(1):208.
Grant TJ, Hua K, Singh A. Molecular pathogenesis of pancreatic cancer. Prog Mol Biol Transl Sci. 2016; 144:241-275.
Grothey A, Fakih M, Tabernero J. Management of BRAF-mutant metastatic colorectal cancer: a review of treatment options and evidence-based guidelines. Ann Oncol. 2021;32(8):959-967.
Hall S, Surova Y, Öhrfelt A; Swedish BioFINDER Study; Blennow K, Zetterberg H, Hansson O. Longitudinal measurements of cerebrospinal fluid biomarkers in parkinson's disease. Mov Disord. 2016;31(6):898-905.
Ham HJ, Lee YS, Yun J, Son DJ, Lee HP, Han SB, Hong JT. K284-6111 alleviates memory impairment and neuroinflammation in Tg2576 mice by inhibition of chitinase-3-like 1 regulating ERK-dependent PTX3 pathway. J Neuroinflammation. 2020;17(1):350.
He CH, Lee CG, Dela Cruz CS, Lee CM, Zhou Y, Ahangari F, Ma B, Herzog EL, Rosenberg SA, Li Y, Nour AM, Parikh CR, Schmidt I, Modis Y, Cantley L, Elias JA. Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor α2. Cell Rep. 2013;4(4):830-41.
He L, Jhong JH, Chen Q, Huang KY, Strittmatter K, Kreuzer J, DeRan M, Wu X, Lee TY, Slavov N, Haas W, Marneros AG. Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors. Cell Rep. 2021;37(5):109955.
Helms EJ, Berry MW, Chaw RC, DuFort CC, Sun D, Onate MK, Oon C, Bhattacharyya S, Sanford-Crane H, Horton W, Finan JM, Sattler A, Makar R, Dawson DW, Xia Z, Hingorani SR, Sherman MH. Mesenchymal lineage heterogeneity underlies nonredundant functions of pancreatic cancer-associated fibroblasts. Cancer Discov. 2022;12(2):484-501.
Hou W, Yi C, Zhu H. Predictive biomarkers of colon cancer immunotherapy: present and future. Front Immunol. 2022; 13:1032314.
Hsi LC, Kundu S, Palomo J, Xu B, Ficco R, Vogelbaum MA, Cathcart MK. Silencing IL-13Rα2 promotes glioblastoma cell death via endogenous signaling. Mol Cancer Ther. 2011;10(7):1149-60.
Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA. Role of LAG-3 in regulatory T cells. Immunity. 2004 ;21(4):503-13.
Ingermann AR, Yang YF, Han J, Mikami A, Garza AE, Mohanraj L, Fan L, Idowu M, Ware JL, Kim HS, Lee DY, Oh Y. Identification of a novel cell death receptor mediating IGFBP-3-induced anti-tumor effects in breast and prostate cancer. J Biol Chem. 2010;285(39):30233-46.
Ishii G, Ochiai A, Neri S. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv Drug Deliv Rev. 2016;99(Pt B):186-196.
Jeon SH, Lee YS, Yeo IJ, Lee HP, Yoon J, Son DJ, Han SB, Hong JT. Inhibition of chitinase-3-like-1 by K284-6111 reduces atopic skin inflammation via repressing lactoferrin. Immune Netw. 2021;21(3): e22.
Joshi R, Ren W, Mathew P. A Bispecific Antibody Targeting the αv and α5β1 integrins induces integrin degradation in prostate cancer cells and is superior to monospecific antibodies. Mol Cancer Res. 2020;18(1):27-32.
Kamath AV. Translational pharmacokinetics and pharmacodynamics of monoclonal antibodies. Drug Discov Today Technol. 2016;21-22:75-83.
Kawada M, Seno H, Kanda K, Nakanishi Y, Akitake R, Komekado H, Kawada K, Sakai Y, Mizoguchi E, Chiba T. Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis in colorectal cancer. Oncogene. 2012;31(26):3111-23.
Keller L, Werner S, Pantel K. Biology and clinical relevance of EpCAM. Cell Stress. 2019;3(6):165-180.
Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141(1):52-67.
Koikawa K, Kibe S, Suizu F, Sekino N, Kim N, Manz TD, Pinch BJ, Akshinthala D, Verma A, Gaglia G, Nezu Y, Ke S, Qiu C, Ohuchida K, Oda Y, Lee TH, Wegiel B, Clohessy JG, London N, Santagata S, Wulf GM, Hidalgo M, Muthuswamy SK, Nakamura M, Gray NS, Zhou XZ, Lu KP. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy. Cell. 2021;184(18):4753-4771.e27.
Kramann R, Menzel S. Mouse models of kidney fibrosis. Methods Mol Biol. 2021; 2299:323-338.
Ku BM, Lee YK, Ryu J, Jeong JY, Choi J, Eun KM, Shin HY, Kim DG, Hwang EM, Yoo JC, Park JY, Roh GS, Kim HJ, Cho GJ, Choi WS, Paek SH, Kang SS. CHI3L1 (YKL-40) is expressed in human gliomas and regulates the invasion, growth and survival of glioma cells. Int J Cancer. 2011;128(6):1316-26.
Landolt L, Spagnoli GC, Hertig A, Brocheriou I, Marti HP. Fibrosis and cancer: shared features and mechanisms suggest common targeted therapeutic approaches. Nephrol Dial Transplant. 2022;37(6):1024-1032.
Lee CM, He CH, Nour AM, Zhou Y, Ma B, Park JW, Kim KH, Dela Cruz C, Sharma L, Nasr ML, Modis Y, Lee CG, Elias JA. IL-13Rα2 uses TMEM219 in chitinase 3-like-1-induced signalling and effector responses. Nat Commun. 2016; 7:12752.
Lee MS, Menter DG, Kopetz S. Right versus left colon cancer biology: integrating the consensus molecular subtypes. J Natl Compr Canc Netw. 2017;15(3):411-419.
Lee YS, Yu JE, Kim KC, Lee DH, Son DJ, Lee HP, Jung JK, Kim ND, Ham YW, Yun J, Han SB, Hong JT. A small molecule targeting CHI3L1 inhibits lung metastasis by blocking IL-13Rα2-mediated JNK-AP-1 signals. Mol Oncol. 2022;16(2):508-526.
Liang KH, Tso HC, Hung SH, Kuan II, Lai JK, Ke FY, Chuang YT, Liu IJ, Wang YP, Chen RH, Wu HC. Extracellular domain of EpCAM enhances tumor progression through EGFR signaling in colon cancer cells. Cancer Lett. 2018; 433:165-175.
Liu T, De Los Santos FG, Phan SH. The bleomycin model of pulmonary fibrosis. Methods Mol Biol. 2017; 1627:27-42.
Lopez-Yrigoyen M, Cassetta L, Pollard JW. Macrophage targeting in cancer. Ann N Y Acad Sci. 2021;1499(1):18-41.
Ma B, Akosman B, Kamle S, Lee CM, He CH, Koo JS, Lee CG, Elias JA. CHI3L1 regulates PD-L1 and anti-CHI3L1-PD-1 antibody elicits synergistic antitumor responses. J Clin Invest. 2021;131(21): e137750.
Ma B, Kamle S, Akosman B, Khan H, Lee CM, Lee CG, Elias JA. CHI3L1 enhances melanoma lung metastasis via regulation of T cell co-stimulators and CTLA-4/B7 axis. Front Immunol. 2022;13: 1056397.
Mace TA, Shakya R, Pitarresi JR, Swanson B, McQuinn CW, Loftus S, Nordquist E, Cruz-Monserrate Z, Yu L, Young G, Zhong X, Zimmers TA, Ostrowski MC, Ludwig T, Bloomston M, Bekaii-Saab T, Lesinski GB. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut. 2018;67(2):320-332.
Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399-416.
Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, Zhang B, Meng Q, Yu X, Shi S. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer. 2021;20(1):131.
Meng XM, Wang S, Huang XR, Yang C, Xiao J, Zhang Y, To KF, Nikolic-Paterson DJ, Lan HY. Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis. Cell Death Dis. 2016;7(12): e2495.
Moffat GT, Epstein AS, O'Reilly EM. Pancreatic cancer-a disease in need: optimizing and integrating supportive care. Cancer. 2019;125(22):3927-3935.
Montgomery TA, Xu L, Mason S, Chinnadurai A, Lee CG, Elias JA, Cantley LG. Breast regression protein-39/chitinase 3-like 1 promotes renal fibrosis after kidney injury via activation of myofibroblasts. J Am Soc Nephrol. 2017;28(11):3218-3226.
Morgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne M, Vignat J, Ferlay J, Murphy N, Bray F. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut. 2023;72(2):338-344.
Nagaoka K, Bai X, Ogawa K, Dong X, Zhang S, Zhou Y, Carlson RI, Jiang ZG, Fuller S, Lebowitz MS, Ghanbari H, Wands JR. Anti-tumor activity of antibody drug conjugate targeting aspartate-β-hydroxylase in pancreatic ductal adenocarcinoma. Cancer Lett. 2019; 449:87-98.
Nishigaki T, Takahashi T, Serada S, Fujimoto M, Ohkawara T, Hara H, Sugase T, Otsuru T, Saito Y, Tsujii S, Nomura T, Tanaka K, Miyazaki Y, Makino T, Kurokawa Y, Nakajima K, Eguchi H, Yamasaki M, Mori M, Doki Y, Naka T. Anti-glypican-1 antibody-drug conjugate is a potential therapy against pancreatic cancer. Br J Cancer. 2020;122(9):1333-1341.
Nishimura N, De Battista D, McGivern DR, Engle RE, Tice A, Fares-Gusmao R, Kabat J, Pomerenke A, Nguyen H, Sato S, Bock KW, Moore IN, Kleiner DE, Zamboni F, Alter HJ, Govindarajan S, Farci P. Chitinase 3-like 1 is a profibrogenic factor overexpressed in the aging liver and in patients with liver cirrhosis. Proc Natl Acad Sci U S A. 2021;118(17): e2019633118.
O'Brien CD, Cao G, Makrigiannakis A, DeLisser HM. Role of immunoreceptor tyrosine-based inhibitory motifs of PECAM-1 in PECAM-1-dependent cell migration. Am J Physiol Cell Physiol. 2004;287(4):C1103-13.
Öhlund 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. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214(3):579-596.
Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci. 2019;110(7):2080-2089.
Park KR, Yun HM, Yoo K, Ham YW, Han SB, Hong JT. Chitinase 3 like 1 suppresses the stability and activity of p53 to promote lung tumorigenesis. Cell Commun Signal. 2020;18(1):5.
Park W, Chawla A, O'Reilly EM. Pancreatic cancer: a review. JAMA. 2021;326(9):851-862.
Philip M, Schietinger A. CD8+ T cell differentiation and dysfunction in cancer. Nat Rev Immunol. 2022;22(4):209-223.
Piersma B, Hayward MK, Weaver VM. Fibrosis and cancer: A strained relationship. Biochim Biophys Acta Rev Cancer. 2020;1873(2):188356.
Qian Y, Gong Y, Fan Z, Luo G, Huang Q, Deng S, Cheng H, Jin K, Ni Q, Yu X, Liu C. Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma. J Hematol Oncol. 2020;13(1):130.
Renkema GH, Boot RG, Au FL, Donker-Koopman WE, Strijland A, Muijsers AO, Hrebicek M, Aerts JM. Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages. Eur J Biochem. 1998;251(1-2):504-9.
Sang L, Coller HA, Roberts JM. Control of the reversibility of cellular quiescence by the transcriptional repressor HES1. Science. 2008;321(5892):1095-100.
Schlüter A, Weller P, Kanaan O, Nel I, Heusgen L, Höing B, Haßkamp P, Zander S, Mandapathil M, Dominas N, Arnolds J, Stuck BA, Lang S, Bankfalvi A, Brandau S. CD31 and VEGF are prognostic biomarkers in early-stage, but not in late-stage, laryngeal squamous cell carcinoma. BMC Cancer. 2018;18(1):272.
Selvanesan BC, Chandra D, Quispe-Tintaya W, Jahangir A, Patel A, Meena K, Alves Da Silva RA, Friedman M, Gabor L, Khouri O, Libutti SK, Yuan Z, Li J, Siddiqui S, Beck A, Tesfa L, Koba W, Chuy J, McAuliffe JC, Jafari R, Entenberg D, Wang Y, Condeelis J, DesMarais V, Balachandran V, Zhang X, Lin K, Gravekamp C. Listeria delivers tetanus toxoid protein to pancreatic tumors and induces cancer cell death in mice. Sci Transl Med. 2022;14(637): eabc1600.
Shao R, Hamel K, Petersen L, Cao QJ, Arenas RB, Bigelow C, Bentley B, Yan W. YKL-40, a secreted glycoprotein, promotes tumor angiogenesis. Oncogene. 2009;28(50):4456-68.
Shelton SE, Nguyen HT, Barbie DA, Kamm RD. Engineering approaches for studying immune-tumor cell interactions and immunotherapy. iScience. 2020;24(1):101985.
Shi Y, Gao W, Lytle NK, Huang P, Yuan X, Dann AM, Ridinger-Saison M, DelGiorno KE, Antal CE, Liang G, Atkins AR, Erikson G, Sun H, Meisenhelder J, Terenziani E, Woo G, Fang L, Santisakultarm TP, Manor U, Xu R, Becerra CR, Borazanci E, Von Hoff DD, Grandgenett PM, Hollingsworth MA, Leblanc M, Umetsu SE, Collisson EA, Scadeng M, Lowy AM, Donahue TR, Reya T, Downes M, Evans RM, Wahl GM, Pawson T, Tian R, Hunter T. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature. 2019;569(7754):131-135.
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48.
Swain SM, Romac JM, Vigna SR, Liddle RA. Piezo1-mediated stellate cell activation causes pressure-induced pancreatic fibrosis in mice. JCI Insight. 2022;7(8): e158288.
Tang PC, Chung JY, Xue VW, Xiao J, Meng XM, Huang XR, Zhou S, Chan AS, Tsang AC, Cheng AS, Lee TL, Leung KT, Lam EW, To KF, Tang PM, Lan HY. Smad3 promotes cancer-associated fibroblasts generation via macrophage-myofibroblast transition. Adv Sci (Weinh). 2022;9(1): e2101235.
The human protein atlas https://www.proteinatlas.org/
Tintelnot J, Stein A. Immunotherapy in colorectal cancer: Available clinical evidence, challenges and novel approaches. World J Gastroenterol. 2019;25(29):3920-3928.
Tiwari A, Trivedi R, Lin SY. Tumor microenvironment: barrier or opportunity towards effective cancer therapy. J Biomed Sci. 2022;29(1):83.
Viallard C, Larrivée B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis. 2017;20(4):409-426.
Vos K, Steenbakkers P, Miltenburg AM, Bos E, van Den Heuvel MW, van Hogezand RA, de Vries RR, Breedveld FC, Boots AM. Raised human cartilage glycoprotein-39 plasma levels in patients with rheumatoid arthritis and other inflammatory conditions. Ann Rheum Dis. 2000;59(7):544-8.
Wang MH, Sun R, Zhou XM, Zhang MY, Lu JB, Yang Y, Zeng LS, Yang XZ, Shi L, Xiao RW, Wang HY, Mai SJ. Epithelial cell adhesion molecule overexpression regulates epithelial-mesenchymal transition, stemness and metastasis of nasopharyngeal carcinoma cells via the PTEN/AKT/mTOR pathway. Cell Death Dis. 2018;9(1):2.
Wang X, Li X, Wei X, Jiang H, Lan C, Yang S, Wang H, Yang Y, Tian C, Xu Z, Zhang J, Hao J, Ren H. PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC. Signal Transduct Target Ther. 2020;5(1):38.
Wang Y, Zhong M, Wang W, Li YH. Chi3l1 regulates APAP-induced liver injury by promoting macrophage infiltration. Eur Rev Med Pharmacol Sci. 2019;23(11):4996-5003.
Watanabe K, Shiga K, Maeda A, Harata S, Yanagita T, Suzuki T, Ushigome H, Maeda Y, Hirokawa T, Ogawa R, Hara M, Takahashi H, Matsuo Y, Mitsui A, Kimura M, Takiguchi S. Chitinase 3-like 1 secreted from cancer-associated fibroblasts promotes tumor angiogenesis via interleukin-8 secretion in colorectal cancer. Int J Oncol. 2022;60(1):3.
Whiteside GT, Kennedy JD. Consideration of pharmacokinetic pharmacodynamic relationships in the discovery of new pain drugs. In: Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton (FL): CRC Press/Taylor & Francis; 2010. Chapter 16.
Wood LD, Canto MI, Jaffee EM, Simeone DM. Pancreatic cancer: pathogenesis, screening, diagnosis, and treatment. Gastroenterology. 2022;163(2):386-402.e1.
Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020;5(1):22.
Xie Z, Gao Y, Ho C, Li L, Jin C, Wang X, Zou C, Mao Y, Wang X, Li Q, Fu D, Zhang YF. Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment. Gut. 2022;71(3):568-579.
Yamauchi M, Barker TH, Gibbons DL, Kurie JM. The fibrotic tumor stroma. J Clin Invest. 2018;128(1):16-25.
Yang PS, Yu MH, Hou YC, Chang CP, Lin SC, Kuo IY, Su PC, Cheng HC, Su WC, Shan YS, Wang YC. Targeting protumor factor chitinase-3-like-1 secreted by Rab37 vesicles for cancer immunotherapy. Theranostics. 2022;12(1):340-361.
Yang X, Fang D, Li M, Chen J, Cheng Y, Luo J. Knockdown of chitinase 3-like-1 inhibits cell proliferation, promotes apoptosis, and enhances effect of anti-programmed death ligand 1 (PD-L1) in diffuse large B cell lymphoma cells. Med Sci Monit. 2021;27: e929431.
Yeh C, Bates SE. Two decades of research toward the treatment of locally advanced and metastatic pancreatic cancer: Remarkable effort and limited gain. Semin Oncol. 2021;48(1):34-46.
Yoshida GJ. Regulation of heterogeneous cancer-associated fibroblasts: the molecular pathology of activated signaling pathways. J Exp Clin Cancer Res. 2020;39(1):112.
Yu JE, Yeo IJ, Son DJ, Yun J, Han SB, Hong JT. Anti-Chi3L1 antibody suppresses lung tumor growth and metastasis through inhibition of M2 polarization. Mol Oncol. 2022;16(11):2214-2234.
Yu MH. Rab37 mediates exocytosis of chitinase 3-like 1 (CHI3L1) in macrophages to promote cancer progression which is blocked by CHI3L1-neutralizing antibody treatment. 2021.
Zhang G, Du YN. Orthotopic pancreatic tumor mouse models of liver metastasis. Methods Mol Biol. 2019; 1882:309-320.
Zhao T, Su Z, Li Y, Zhang X, You Q. Chitinase-3 like-protein-1 function and its role in diseases. Signal Transduct Target Ther. 2020;5(1):201.
Zhao Z, Wang L, Xu W. IL-13Rα2 mediates PNR-induced migration and metastasis in ERα-negative breast cancer. Oncogene. 2015;34(12):1596-607.
Zheng M, Cai WM, Zhao JK, Zhu SM, Liu RH. Determination of serum levels of YKL-40 and hyaluronic acid in patients with hepatic fibrosis due to schistosomiasis japonica and appraisal of their clinical value. Acta Trop. 2005;96(2-3):148-52.
Zhou Y, He CH, Herzog EL, Peng X, Lee CM, Nguyen TH, Gulati M, Gochuico BR, Gahl WA, Slade ML, Lee CG, Elias JA. Chitinase 3-like-1 and its receptors in Hermansky-Pudlak syndrome-associated lung disease. J Clin Invest. 2015;125(8):3178-92.
Zhou Y, He CH, Yang DS, Nguyen T, Cao Y, Kamle S, Lee CM, Gochuico BR, Gahl WA, Shea BS, Lee CG, Elias JA. Galectin-3 Interacts with the CHI3L1 Axis and Contributes to Hermansky-Pudlak Syndrome Lung Disease. J Immunol. 2018;200(6):2140-2153.
Zhou Y, Peng H, Sun H, Peng X, Tang C, Gan Y, Chen X, Mathur A, Hu B, Slade MD, Montgomery RR, Shaw AC, Homer RJ, White ES, Lee CM, Moore MW, Gulati M, Lee CG, Elias JA, Herzog EL. Chitinase 3-like 1 suppresses injury and promotes fibroproliferative responses in mammalian lung fibrosis. Sci Transl Med. 2014;6(240):240ra76.
Zhu G, Pei L, Xia H, Tang Q, Bi F. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Mol Cancer. 2021;20(1):143.