Role of heterogeneity of cancer-associated fibroblasts in targeted therapy of pancreatic cancer

Abstract

Abstract:

The incidence of pancreatic cancer is increasing year by year, but the clinical diagnosis and treatment progress is limited and the prognosis is poor. Tumor microenvironment (TME) is closely related to the invasion, metastasis and chemotherapy resistance of pancreatic cancer. Cancer-associated fibroblasts (CAFs) are fibroblasts in a state of continuous activation, which are the most prominent components in TME. CAFs can promote the malignant biological behavior of pancreatic cancer through a variety of molecule-mediated mechanisms. Moreover, several attempts targeting CAFs for the treatment of pancreatic cancer have been largely unsuccessful. It may be related to the heterogeneity of CAFs in pancreatic cancer. Therefore, in-depth study of its heterogeneity and accurate targeting of some specific phenotypes and functional CAFs subtypes in the matrix on this basis may be more promising in the clinical treatment of pancreatic cancer.

Key words:Cancer-associated fibroblasts,Tumor microenvironment,Molecular targeted therapy,Pancreatic neoplasms

Yan Zhiying, Mao Yifeng, Zhu Yingwei, Xu Kequn. Role of heterogeneity of cancer-associated fibroblasts in targeted therapy of pancreatic cancer[J]. Journal of International Oncology, 2021, 48(5): 308-312.

References35

[1]	Kamisawa T, Wood LD, Itoi T, et al. Pancreatic cancer[J]. Lancet, 2016,388(10039):73-85. DOI: 10.1016/S0140-6736(16)00141-0. doi:10.1016/S0140-6736(16)00141-0pmid:26830752
[2]	Tian C, Clauser KR, Öhlund D, et al. Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells[J]. Proc Natl Acad Sci U S A, 2019,116(39):19609-19618. DOI: 10.1073/pnas.1908626116. doi:10.1073/pnas.1908626116
[3]	Neesse A, Bauer CA, Öhlund D, et al. Stromal biology and therapy in pancreatic cancer: ready for clinical translation?[J]. Gut, 2019,68(1):159-171. DOI: 10.1136/gutjnl-2018-316451. doi:10.1136/gutjnl-2018-316451
[4]	Özdemir BC, Pentcheva-Hoang T, Carstens JL, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival[J]. Cancer Cell, 2015,28(6):831-833. DOI: 10.1016/j.ccell.2015.11.002. doi:S1535-6108(15)00423-7pmid:28843279
[5]	Rhim AD, Oberstein PE, Thomas DH, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma[J]. Cancer Cell, 2014,25(6):735-747. DOI: 10.1016/j.ccr.2014.04.021. doi:10.1016/j.ccr.2014.04.021
[6]	Neuzillet C, Tijeras-Raballand A, Ragulan C, et al. Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma[J]. J Pathol, 2019,248(1):51-65. DOI: 10.1002/path.5224. doi:10.1002/path.2019.248.issue-1
[7]	Arina A, Idel C, Hyjek EM, et al. Tumor-associated fibroblasts predominantly come from local and not circulating precursors[J]. Proc Natl Acad Sci U S A, 2016,113(27):7551-7556. DOI: 10.1073/pnas.1600363113. doi:10.1073/pnas.1600363113
[8]	Biffi G, Oni TE, Spielman B, et al. IL1-induced JAK/STAT signaling is antagonized by TGF-β to shape CAF heterogeneity in pancreatic ductal adenocarcinoma[J]. Cancer Discov, 2019,9(2):282-301. DOI: 10.1158/2159-8290.CD-18-0710. doi:10.1158/2159-8290.CD-18-0710
[9]	Wörmann SM, Song L, Ai J, et al. Loss of P53 function activates JAK2-STAT3 signaling to promote pancreatic tumor growth, stroma modification, and gemcitabine resistance in mice and is associated with patient survival[J]. Gastroenterology, 2016,151(1):180-193. DOI: 10.1053/j.gastro.2016.03.010. doi:10.1053/j.gastro.2016.03.010pmid:27003603
[10]	Novo D, Heath N, Mitchell L, et al. Mutant p53s generate proinvasive niches by influencing exosome podocalyxin levels[J]. Nat Commun, 2018,9(1):5069. DOI: 10.1038/s41467-018-07339-y. doi:10.1038/s41467-018-07339-y
[11]	Vennin C, Mélénec P, Rouet R, et al. CAF hierarchy driven by pancreatic cancer cell p53-status creates a prometastatic and chemoresistant environment via perlecan[J]. Nat Commun, 2019,10(1):3637. DOI: 10.1038/s41467-019-10968-6. doi:10.1038/s41467-019-10968-6
[12]	Pidsley R, Lawrence MG, Zotenko E, et al. Enduring epigenetic landmarks define the cancer microenvironment[J]. Genome Res, 2018,28(5):625-638. DOI: 10.1101/gr.229070.117. doi:10.1101/gr.229070.117
[13]	Xiao Q, Zhou D, Rucki AA, et al. Cancer-associated fibroblasts in pancreatic cancer are reprogrammed by tumorinduced alterations in genomic DNA methylation[J]. Cancer Res, 2016,76(18):5395-5404. DOI: 10.1158/0008-5472.CAN-15-3264. doi:10.1158/0008-5472.CAN-15-3264
[14]	Öhlund D, Handly-Santana A, Biffi G, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer[J]. J Exp Med, 2017,214(3):579-596. DOI: 10.1084/jem.20162024. doi:10.1084/jem.20162024
[15]	Elyada E, Bolisetty M, Laise P, et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts[J]. Cancer Discov, 2019,9(8):1102-1123. DOI: 10.1158/2159-8290.CD-19-0094. doi:10.1158/2159-8290.CD-19-0094pmid:31197017
[16]	Shan T, Lu H, Ji H, et al. Loss of stromal caveolin-1 expression: a novel tumor microenvironment biomarker that can predict poor clinical outcomes for pancreatic cancer[J]. PLoS One, 2014,9(6):e97239. DOI: 10.1371/journal.pone.0097239. doi:10.1371/journal.pone.0097239
[17]	Maruggi M, Layng FI, Lemos R Jr, et al. Absence of HIF1A leads to glycogen accumulation and an inflammatory response that enables pancreatic tumor growth[J]. Cancer Res, 2019,79(22):5839-5848. DOI: 10.1158/0008-5472.CAN-18-2994. doi:10.1158/0008-5472.CAN-18-2994
[18]	Feig C, Jones JO, Kraman M, et al. Targeting CXCL12 from FAP expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer[J]. Proc Natl Acad Sci U S A, 2013,110(50):20212-20217. DOI: 10.1073/pnas.1320318110. doi:10.1073/pnas.1320318110
[19]	Lo A, Wang LS, Scholler J, et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells[J]. Cancer Res, 2015,75(14):2800-2810. DOI: 10.1158/0008-5472.CAN-14-3041. doi:10.1158/0008-5472.CAN-14-3041
[20]	Su S, Chen J, Yao H, et al. CD10⁺GPR77⁺cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness[J]. Cell, 2018,172(4):841-856. DOI: 10.1016/j.cell.2018.01.009. doi:10.1016/j.cell.2018.01.009
[21]	Han X, Li Y, Xu Y, et al. Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem[J]. Nat Commun, 2018,9(1):3390. DOI: 10.1038/s41467-018-05906-x. doi:10.1038/s41467-018-05906-x
[22]	Sherman MH, Yu RT, Engle DD, et al. Vitamin D receptormedia-ted stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy[J]. Cell, 2014,159(1):80-93. DOI: 10.1016/j.cell.2014.08.007. doi:S0092-8674(14)01033-2pmid:25259922
[23]	Dauer P, Zhao X, Gupta VK, et al. Inactivation of cancerassocia-ted-fibroblasts disrupts oncogenic signaling in pancreatic cancer cells and promotes its regression[J]. Cancer Res, 2018,78(5):1321-1333. DOI: 10.1158/0008-5472.CAN-17-2320. doi:10.1158/0008-5472.CAN-17-2320
[24]	Schnittert J, Heinrich MA, Kuninty PR, et al. Reprogramming tumor stroma using an endogenous lipid lipoxin A4 to treat pancreatic cancer[J]. Cancer Lett, 2018,420:247-258. DOI: 10.1016/j.canlet.2018.01.072. doi:10.1016/j.canlet.2018.01.072
[25]	Djurec M, Graña O, Lee A, et al. Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors[J]. Proc Natl Acad Sci U S A, 2018,115(6):E1147-E1156. DOI: 10.1073/pnas.1717802115. doi:10.1073/pnas.1717802115
[26]	Whatcott CJ, Ng S, Barrett MT, et al. Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic can-cer[J]. PLoS One, 2017,12(8):e0183871. DOI: 10.1371/journal.pone.0183871. doi:10.1371/journal.pone.0183871
[27]	Johnson DE, O'Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer[J]. Nat Rev Clin Oncol, 2018,15(4):234-248. DOI: 10.1038/nrclinonc.2018.8. doi:10.1038/nrclinonc.2018.8pmid:29405201
[28]	Shi Y, Gao W, Lytle NK, et al. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring[J]. Nature, 2019,569(7754):131-135. DOI: 10.1038/s41586-019-1130-6. doi:10.1038/s41586-019-1130-6pmid:30996350
[29]	Pinho AV, Van Bulck M, Chantrill L, et al. ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling[J]. Nat Commun, 2018,9(1):5083. DOI: 10.1038/s41467-018-07497-z. doi:10.1038/s41467-018-07497-z
[30]	Yang Y, Andersson P, Hosaka K, et al. The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages[J]. Nat Commun, 2016,7:11385. DOI: 10.1038/ncomms11385. doi:10.1038/ncomms11385
[31]	Steele CW, Karim SA, Leach JDG, et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma[J]. Cancer Cell, 2016,29(6):832-845. DOI: 10.1016/j.ccell.2016.04.014. doi:S1535-6108(16)30203-3pmid:27265504
[32]	Duluc C, Moatassim-Billah S, Chalabi-Dchar M, et al. Pharmacological targeting of the protein synjournal mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumour chemoresistance[J]. EMBO Mol Med, 2015,7(6):735-753. DOI: 10.15252/emmm.201404346. doi:10.15252/emmm.201404346
[33]	Ko AH, LoConte N, Tempero MA, et al. A Phase Ⅰ study of FOLFIRINOX plus IPI-926, a Hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma[J]. Pancreas, 2016,45(3):370-375. DOI: 10.1097/MPA.0000000000000458. doi:10.1097/MPA.0000000000000458
[34]	Hingorani SR, Zheng L, Bullock AJ, et al. HALO 202: randomized phase Ⅱ study of PEGPH20 plus nabpaclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma[J]. J Clin Oncol, 2018,36(4):359-366. DOI: 10.1200/JCO.2017.74.9564.
[35]	Miller BW, Morton JP, Pinese M, et al. Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy[J]. EMBO Mol Med, 2015,7(8):1063-1076. DOI: 10.15252/emmm.201404827. doi:10.15252/emmm.201404827pmid:26077591