Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment
Abstract
:Simple Summary
Abstract
1. Introduction
2. Molecular Landscape of Pancreatic Cancer
3. Current Standards of Care
4. Targeting Pancreatic Tumor Microenvironment (TME)
4.1. Pancreatic Stellate Cells
4.2. Cancer-Associated Fibroblasts
4.3. Tumor-Associated Macrophages
4.4. Tumor-Asociated Neutrophils
4.5. Myeloid-Derived Suppressor Cells
4.6. Regulatory T Cells
5. Pancreatic Cancer Progression and Resistance: The Role of the Tumor Microenvironment
6. Targeted Precision Therapies
6.1. Targeting Fibrosis in TME
6.2. Targeting TME Immune Cells
6.3. Targeting Epithelial-to-Mesenchymal Transition
6.4. Targeting Exosomes in the TME
6.5. Other Precision TME Targeting Strategies
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Klein, A.P. Pancreatic cancer epidemiology: Understanding the role of lifestyle and inherited risk factors. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 493–502. [Google Scholar] [CrossRef] [PubMed]
- Jiang, S.; Fagman, J.B.; Ma, Y.; Liu, J.; Vihav, C.; Engstrom, C.; Liu, B.; Chen, C. A comprehensive review of pancreatic cancer and its therapeutic challenges. Aging 2022, 14, 7635–7649. [Google Scholar] [CrossRef] [PubMed]
- Klatte, D.C.F.; Wallace, M.B.; Lohr, M.; Bruno, M.J.; van Leerdam, M.E. Hereditary pancreatic cancer. Best Pract. Res. Clin. Gastroenterol. 2022, 58–59, 101783. [Google Scholar] [CrossRef] [PubMed]
- Kolbeinsson, H.M.; Chandana, S.; Wright, G.P.; Chung, M. Pancreatic Cancer: A Review of Current Treatment and Novel Therapies. J. Investig. Surg. 2023, 36, 2129884. [Google Scholar] [CrossRef] [PubMed]
- Zhao, Z.; Liu, W. Pancreatic Cancer: A Review of Risk Factors, Diagnosis, and Treatment. Technol. Cancer Res. Treat. 2020, 19, 1533033820962117. [Google Scholar] [CrossRef] [PubMed]
- Wood, L.D.; Canto, M.I.; Jaffee, E.M.; Simeone, D.M. Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment. Gastroenterology 2022, 163, 386–402.e1. [Google Scholar] [CrossRef] [PubMed]
- Oyama, H.; Tada, M.; Takagi, K.; Tateishi, K.; Hamada, T.; Nakai, Y.; Hakuta, R.; Ijichi, H.; Ishigaki, K.; Kanai, S.; et al. Long-term Risk of Malignancy in Branch-Duct Intraductal Papillary Mucinous Neoplasms. Gastroenterology 2020, 158, 226–237.e5. [Google Scholar] [CrossRef]
- Rezaee, N.; Barbon, C.; Zaki, A.; He, J.; Salman, B.; Hruban, R.H.; Cameron, J.L.; Herman, J.M.; Ahuja, N.; Lennon, A.M.; et al. Intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia is a risk factor for the subsequent development of pancreatic ductal adenocarcinoma. HPB 2016, 18, 236–246. [Google Scholar] [CrossRef] [PubMed]
- Raptis, D.A.; Fessas, C.; Belasyse-Smith, P.; Kurzawinski, T.R. Clinical presentation and waiting time targets do not affect prognosis in patients with pancreatic cancer. Surgeon 2010, 8, 239–246. [Google Scholar] [CrossRef] [PubMed]
- Groot, V.P.; Gemenetzis, G.; Blair, A.B.; Ding, D.; Javed, A.A.; Burkhart, R.A.; Yu, J.; Borel Rinkes, I.H.; Molenaar, I.Q.; Cameron, J.L.; et al. Implications of the Pattern of Disease Recurrence on Survival Following Pancreatectomy for Pancreatic Ductal Adenocarcinoma. Ann. Surg. Oncol. 2018, 25, 2475–2483. [Google Scholar] [CrossRef] [PubMed]
- Wangjam, T.; Zhang, Z.; Zhou, X.C.; Lyer, L.; Faisal, F.; Soares, K.C.; Fishman, E.; Hruban, R.H.; Herman, J.M.; Laheru, D.; et al. Resected pancreatic ductal adenocarcinomas with recurrence limited in lung have a significantly better prognosis than those with other recurrence patterns. Oncotarget 2015, 6, 36903–36910. [Google Scholar] [CrossRef] [PubMed]
- Von Hoff, D.D.; Ervin, T.; Arena, F.P.; Chiorean, E.G.; Infante, J.; Moore, M.; Seay, T.; Tjulandin, S.A.; Ma, W.W.; Saleh, M.N.; et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 2013, 369, 1691–1703. [Google Scholar] [CrossRef]
- Torphy, R.J.; Fujiwara, Y.; Schulick, R.D. Pancreatic cancer treatment: Better, but a long way to go. Surg. Today 2020, 50, 1117–1125. [Google Scholar] [CrossRef]
- Halbrook, C.J.; Lyssiotis, C.A.; Pasca di Magliano, M.; Maitra, A. Pancreatic cancer: Advances and challenges. Cell 2023, 186, 1729–1754. [Google Scholar] [CrossRef]
- Hinshaw, D.C.; Shevde, L.A. The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Res. 2019, 79, 4557–4566. [Google Scholar] [CrossRef] [PubMed]
- Brunner, M.; Wu, Z.; Krautz, C.; Pilarsky, C.; Grutzmann, R.; Weber, G.F. Current Clinical Strategies of Pancreatic Cancer Treatment and Open Molecular Questions. Int. J. Mol. Sci. 2019, 20, 4543. [Google Scholar] [CrossRef]
- Conroy, T.; Bachet, J.B.; Ayav, A.; Huguet, F.; Lambert, A.; Caramella, C.; Marechal, R.; Van Laethem, J.L.; Ducreux, M. Current standards and new innovative approaches for treatment of pancreatic cancer. Eur. J. Cancer 2016, 57, 10–22. [Google Scholar] [CrossRef]
- Grutzmann, R.; Boriss, H.; Ammerpohl, O.; Luttges, J.; Kalthoff, H.; Schackert, H.K.; Kloppel, G.; Saeger, H.D.; Pilarsky, C. Meta-analysis of microarray data on pancreatic cancer defines a set of commonly dysregulated genes. Oncogene 2005, 24, 5079–5088. [Google Scholar] [CrossRef] [PubMed]
- Pon, J.R.; Marra, M.A. Driver and passenger mutations in cancer. Annu. Rev. Pathol. 2015, 10, 25–50. [Google Scholar] [CrossRef]
- Kamisawa, T.; Wood, L.D.; Itoi, T.; Takaori, K. Pancreatic cancer. Lancet 2016, 388, 73–85. [Google Scholar] [CrossRef]
- Hezel, A.F.; Kimmelman, A.C.; Stanger, B.Z.; Bardeesy, N.; Depinho, R.A. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2006, 20, 1218–1249. [Google Scholar] [CrossRef] [PubMed]
- Ciner, A.T.; Jiang, Y.; Hausner, P. BRAF-Driven Pancreatic Cancer: Prevalence, Molecular Features, and Therapeutic Opportunities. Mol. Cancer Res. 2023, 21, 293–300. [Google Scholar] [CrossRef] [PubMed]
- Molin, M.D.; Matthaei, H.; Wu, J.; Blackford, A.; Debeljak, M.; Rezaee, N.; Wolfgang, C.L.; Butturini, G.; Salvia, R.; Bassi, C.; et al. Clinicopathological correlates of activating GNAS mutations in intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Ann. Surg. Oncol. 2013, 20, 3802–3808. [Google Scholar] [CrossRef] [PubMed]
- Ng, C.F.; Glaspy, J.; Placencio-Hickok, V.R.; Thomassian, S.; Gong, J.; Osipov, A.; Hendifar, A.E.; Moshayedi, N. Exceptional Response to Erdafitinib in FGFR2-Mutated Metastatic Pancreatic Ductal Adenocarcinoma. J. Natl. Compr. Cancer Netw. 2022, 20, 1076–1079. [Google Scholar] [CrossRef] [PubMed]
- Zeng, G.; Germinaro, M.; Micsenyi, A.; Monga, N.K.; Bell, A.; Sood, A.; Malhotra, V.; Sood, N.; Midda, V.; Monga, D.K.; et al. Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma. Neoplasia 2006, 8, 279–289. [Google Scholar] [CrossRef] [PubMed]
- Caldas, C.; Hahn, S.A.; da Costa, L.T.; Redston, M.S.; Schutte, M.; Seymour, A.B.; Weinstein, C.L.; Hruban, R.H.; Yeo, C.J.; Kern, S.E. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat. Genet. 1994, 8, 27–32. [Google Scholar] [CrossRef] [PubMed]
- Cicenas, J.; Kvederaviciute, K.; Meskinyte, I.; Meskinyte-Kausiliene, E.; Skeberdyte, A.; Cicenas, J. KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 Mutations in Pancreatic Cancer. Cancers 2017, 9, 42. [Google Scholar] [CrossRef] [PubMed]
- Iacobuzio-Donahue, C.A.; Song, J.; Parmiagiani, G.; Yeo, C.J.; Hruban, R.H.; Kern, S.E. Missense mutations of MADH4: Characterization of the mutational hot spot and functional consequences in human tumors. Clin. Cancer Res. 2004, 10, 1597–1604. [Google Scholar] [CrossRef] [PubMed]
- Dancer, J.; Takei, H.; Ro, J.Y.; Lowery-Nordberg, M. Coexpression of EGFR and HER-2 in pancreatic ductal adenocarcinoma: A comparative study using immunohistochemistry correlated with gene amplification by fluorescencent in situ hybridization. Oncol. Rep. 2007, 18, 151–155. [Google Scholar] [CrossRef] [PubMed]
- Reshkin, S.J.; Cardone, R.A.; Koltai, T. Genetic Signature of Human Pancreatic Cancer and Personalized Targeting. Cells 2024, 13, 602. [Google Scholar] [CrossRef] [PubMed]
- Collisson, E.A.; Bailey, P.; Chang, D.K.; Biankin, A.V. Molecular subtypes of pancreatic cancer. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 207–220. [Google Scholar] [CrossRef] [PubMed]
- Connor, A.A.; Denroche, R.E.; Jang, G.H.; Lemire, M.; Zhang, A.; Chan-Seng-Yue, M.; Wilson, G.; Grant, R.C.; Merico, D.; Lungu, I.; et al. Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases. Cancer Cell 2019, 35, 267–282.e7. [Google Scholar] [CrossRef] [PubMed]
- Felsenstein, M.; Hruban, R.H.; Wood, L.D. New Developments in the Molecular Mechanisms of Pancreatic Tumorigenesis. Adv. Anat. Pathol. 2018, 25, 131–142. [Google Scholar] [CrossRef] [PubMed]
- Shen, G.Q.; Aleassa, E.M.; Walsh, R.M.; Morris-Stiff, G. Next-Generation Sequencing in Pancreatic Cancer. Pancreas 2019, 48, 739–748. [Google Scholar] [CrossRef] [PubMed]
- Ying, H.; Dey, P.; Yao, W.; Kimmelman, A.C.; Draetta, G.F.; Maitra, A.; DePinho, R.A. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2016, 30, 355–385. [Google Scholar] [CrossRef] [PubMed]
- Adsay, N.V.; Basturk, O.; Cheng, J.D.; Andea, A.A. Ductal neoplasia of the pancreas: Nosologic, clinicopathologic, and biologic aspects. Semin. Radiat. Oncol. 2005, 15, 254–264. [Google Scholar] [CrossRef] [PubMed]
- Makohon-Moore, A.; Iacobuzio-Donahue, C.A. Pancreatic cancer biology and genetics from an evolutionary perspective. Nat. Rev. Cancer 2016, 16, 553–565. [Google Scholar] [CrossRef]
- Hu, H.F.; Ye, Z.; Qin, Y.; Xu, X.W.; Yu, X.J.; Zhuo, Q.F.; Ji, S.R. Mutations in key driver genes of pancreatic cancer: Molecularly targeted therapies and other clinical implications. Acta Pharmacol. Sin. 2021, 42, 1725–1741. [Google Scholar] [CrossRef] [PubMed]
- Guerra, C.; Barbacid, M. Genetically engineered mouse models of pancreatic adenocarcinoma. Mol. Oncol. 2013, 7, 232–247. [Google Scholar] [CrossRef]
- Vitorakis, N.; Piperi, C. Insights into the Role of Histone Methylation in Brain Aging and Potential Therapeutic Interventions. Int. J. Mol. Sci. 2023, 24, 17339. [Google Scholar] [CrossRef]
- Ling, Q.; Kalthoff, H. Transportome Malfunctions and the Hallmarks of Pancreatic Cancer. Rev. Physiol. Biochem. Pharmacol. 2021, 181, 105–127. [Google Scholar] [CrossRef] [PubMed]
- Li, X.; Liang, M.; Jiang, J.; He, R.; Wang, M.; Guo, X.; Shen, M.; Qin, R. Combined inhibition of autophagy and Nrf2 signaling augments bortezomib-induced apoptosis by increasing ROS production and ER stress in pancreatic cancer cells. Int. J. Biol. Sci. 2018, 14, 1291–1305. [Google Scholar] [CrossRef] [PubMed]
- Wu, Y.S.; Looi, C.Y.; Subramaniam, K.S.; Masamune, A.; Chung, I. Soluble factors from stellate cells induce pancreatic cancer cell proliferation via Nrf2-activated metabolic reprogramming and ROS detoxification. Oncotarget 2016, 7, 36719–36732. [Google Scholar] [CrossRef] [PubMed]
- Feng, R.; Morine, Y.; Ikemoto, T.; Imura, S.; Iwahashi, S.; Saito, Y.; Shimada, M. Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction. Cell Commun. Signal. 2018, 16, 54. [Google Scholar] [CrossRef] [PubMed]
- Duong, H.Q.; Yi, Y.W.; Kang, H.J.; Hong, Y.B.; Tang, W.; Wang, A.; Seong, Y.S.; Bae, I. Inhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine. Int. J. Oncol. 2014, 44, 959–969. [Google Scholar] [CrossRef] [PubMed]
- Duong, H.Q.; You, K.S.; Oh, S.; Kwak, S.J.; Seong, Y.S. Silencing of NRF2 Reduces the Expression of ALDH1A1 and ALDH3A1 and Sensitizes to 5-FU in Pancreatic Cancer Cells. Antioxidants 2017, 6, 52. [Google Scholar] [CrossRef] [PubMed]
- Gao, L.; Xu, Z.; Huang, Z.; Tang, Y.; Yang, D.; Huang, J.; He, L.; Liu, M.; Chen, Z.; Teng, Y. CPI-613 rewires lipid metabolism to enhance pancreatic cancer apoptosis via the AMPK-ACC signaling. J. Exp. Clin. Cancer Res. 2020, 39, 73. [Google Scholar] [CrossRef] [PubMed]
- Park, T.H.; Kim, H.S. Eupatilin Suppresses Pancreatic Cancer Cells via Glucose Uptake Inhibition, AMPK Activation, and Cell Cycle Arrest. Anticancer Res. 2022, 42, 483–491. [Google Scholar] [CrossRef] [PubMed]
- Lin, R.; Bao, X.; Wang, H.; Zhu, S.; Liu, Z.; Chen, Q.; Ai, K.; Shi, B. TRPM2 promotes pancreatic cancer by PKC/MAPK pathway. Cell Death Dis. 2021, 12, 585. [Google Scholar] [CrossRef] [PubMed]
- Sheng, W.; Shi, X.; Lin, Y.; Tang, J.; Jia, C.; Cao, R.; Sun, J.; Wang, G.; Zhou, L.; Dong, M. Musashi2 promotes EGF-induced EMT in pancreatic cancer via ZEB1-ERK/MAPK signaling. J. Exp. Clin. Cancer Res. 2020, 39, 16. [Google Scholar] [CrossRef] [PubMed]
- Ouyang, L.; Liu, R.D.; Lei, D.Q.; Shang, Q.C.; Li, H.F.; Hu, X.G.; Zheng, H.; Jin, G. MiR-499a-5p promotes 5-FU resistance and the cell proliferation and migration through activating PI3K/Akt signaling by targeting PTEN in pancreatic cancer. Ann. Transl. Med. 2021, 9, 1798. [Google Scholar] [CrossRef]
- Zhao, F.; Yang, G.; Qiu, J.; Liu, Y.; Tao, J.; Chen, G.; Su, D.; You, L.; Zheng, L.; Zhang, T.; et al. HIF-1alpha-regulated stanniocalcin-1 mediates gemcitabine resistance in pancreatic ductal adenocarcinoma via PI3K/AKT signaling pathway. Mol. Carcinog. 2022, 61, 839–850. [Google Scholar] [CrossRef] [PubMed]
- Zhou, H.; Yun, X.; Shu, Y.; Xu, K. Aspirin increases the efficacy of gemcitabine in pancreatic cancer by modulating the PI3K/AKT/mTOR signaling pathway and reversing epithelial-mesenchymal transition. Oncol. Lett. 2023, 25, 101. [Google Scholar] [CrossRef] [PubMed]
- Chen, H.; Zhou, W.; Bian, A.; Zhang, Q.; Miao, Y.; Yin, X.; Ye, J.; Xu, S.; Ti, C.; Sun, Z.; et al. Selectively Targeting STAT3 Using a Small Molecule Inhibitor is a Potential Therapeutic Strategy for Pancreatic Cancer. Clin. Cancer Res. 2023, 29, 815–830. [Google Scholar] [CrossRef] [PubMed]
- Hubbard, J.M.; Grothey, A. Napabucasin: An Update on the First-in-Class Cancer Stemness Inhibitor. Drugs 2017, 77, 1091–1103. [Google Scholar] [CrossRef] [PubMed]
- Du, W.; Menjivar, R.E.; Donahue, K.L.; Kadiyala, P.; Velez-Delgado, A.; Brown, K.L.; Watkoske, H.R.; He, X.; Carpenter, E.S.; Angeles, C.V.; et al. WNT signaling in the tumor microenvironment promotes immunosuppression in murine pancreatic cancer. J. Exp. Med. 2023, 220, e20220503. [Google Scholar] [CrossRef] [PubMed]
- Mirzaei, S.; Zarrabi, A.; Hashemi, F.; Zabolian, A.; Saleki, H.; Ranjbar, A.; Seyed Saleh, S.H.; Bagherian, M.; Sharifzadeh, S.O.; Hushmandi, K.; et al. Regulation of Nuclear Factor-KappaB (NF-kappaB) signaling pathway by non-coding RNAs in cancer: Inhibiting or promoting carcinogenesis? Cancer Lett. 2021, 509, 63–80. [Google Scholar] [CrossRef] [PubMed]
- Ashrafizaveh, S.; Ashrafizadeh, M.; Zarrabi, A.; Husmandi, K.; Zabolian, A.; Shahinozzaman, M.; Aref, A.R.; Hamblin, M.R.; Nabavi, N.; Crea, F.; et al. Long non-coding RNAs in the doxorubicin resistance of cancer cells. Cancer Lett. 2021, 508, 104–114. [Google Scholar] [CrossRef] [PubMed]
- Ashrafizadeh, M.; Mohan, C.D.; Rangappa, S.; Zarrabi, A.; Hushmandi, K.; Kumar, A.P.; Sethi, G.; Rangappa, K.S. Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: Roles in cancer progression and therapeutic response. Med. Res. Rev. 2023, 43, 1263–1321. [Google Scholar] [CrossRef] [PubMed]
- Gu, M.; Liu, Y.; Xin, P.; Guo, W.; Zhao, Z.; Yang, X.; Ma, R.; Jiao, T.; Zheng, W. Fundamental insights and molecular interactions in pancreatic cancer: Pathways to therapeutic approaches. Cancer Lett. 2024, 588, 216738. [Google Scholar] [CrossRef] [PubMed]
- Park, S.J.; Jang, S.; Han, J.K.; Kim, H.; Kwon, W.; Jang, J.Y.; Lee, K.B.; Kim, H.; Lee, D.H. Preoperative assessment of the resectability of pancreatic ductal adenocarcinoma on CT according to the NCCN Guidelines focusing on SMA/SMV branch invasion. Eur. Radiol. 2021, 31, 6889–6897. [Google Scholar] [CrossRef] [PubMed]
- Strobel, O.; Lorenz, P.; Hinz, U.; Gaida, M.; Konig, A.K.; Hank, T.; Niesen, W.; Kaiser, J.O.R.; Al-Saeedi, M.; Bergmann, F.; et al. Actual Five-year Survival After Upfront Resection for Pancreatic Ductal Adenocarcinoma: Who Beats the Odds? Ann. Surg. 2022, 275, 962–971. [Google Scholar] [CrossRef] [PubMed]
- Conroy, T.; Hammel, P.; Hebbar, M.; Ben Abdelghani, M.; Wei, A.C.; Raoul, J.L.; Chone, L.; Francois, E.; Artru, P.; Biagi, J.J.; et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N. Engl. J. Med. 2018, 379, 2395–2406. [Google Scholar] [CrossRef] [PubMed]
- Manji, G.A.; Olive, K.P.; Saenger, Y.M.; Oberstein, P. Current and Emerging Therapies in Metastatic Pancreatic Cancer. Clin. Cancer Res. 2017, 23, 1670–1678. [Google Scholar] [CrossRef] [PubMed]
- Chin, V.; Nagrial, A.; Sjoquist, K.; O’Connor, C.A.; Chantrill, L.; Biankin, A.V.; Scholten, R.J.; Yip, D. Chemotherapy and radiotherapy for advanced pancreatic cancer. Cochrane Database Syst. Rev. 2018, 3, CD011044. [Google Scholar] [CrossRef] [PubMed]
- Rombouts, S.J.; Walma, M.S.; Vogel, J.A.; van Rijssen, L.B.; Wilmink, J.W.; Mohammad, N.H.; van Santvoort, H.C.; Molenaar, I.Q.; Besselink, M.G. Systematic Review of Resection Rates and Clinical Outcomes after FOLFIRINOX-Based Treatment in Patients with Locally Advanced Pancreatic Cancer. Ann. Surg. Oncol. 2016, 23, 4352–4360. [Google Scholar] [CrossRef] [PubMed]
- Gugenheim, J.; Crovetto, A.; Petrucciani, N. Neoadjuvant therapy for pancreatic cancer. Updates Surg. 2022, 74, 35–42. [Google Scholar] [CrossRef] [PubMed]
- Janssen, Q.P.; van Dam, J.L.; Bonsing, B.A.; Bos, H.; Bosscha, K.P.; Coene, P.; van Eijck, C.H.J.; de Hingh, I.; Karsten, T.M.; van der Kolk, M.B.; et al. Total neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for resectable and borderline resectable pancreatic cancer (PREOPANC-2 trial): Study protocol for a nationwide multicenter randomized controlled trial. BMC Cancer 2021, 21, 300. [Google Scholar] [CrossRef]
- Carnevale, J.; Ko, A.H. MM-398 (nanoliposomal irinotecan): Emergence of a novel therapy for the treatment of advanced pancreatic cancer. Future Oncol. 2016, 12, 453–464. [Google Scholar] [CrossRef] [PubMed]
- Kluger, M.D.; Rashid, M.F.; Rosario, V.L.; Schrope, B.A.; Steinman, J.A.; Hecht, E.M.; Chabot, J.A. Resection of Locally Advanced Pancreatic Cancer without Regression of Arterial Encasement After Modern-Era Neoadjuvant Therapy. J. Gastrointest. Surg. 2018, 22, 235–241. [Google Scholar] [CrossRef] [PubMed]
- Chiang, N.J.; Chang, J.Y.; Shan, Y.S.; Chen, L.T. Development of nanoliposomal irinotecan (nal-IRI, MM-398, PEP02) in the management of metastatic pancreatic cancer. Expert Opin. Pharmacother. 2016, 17, 1413–1420. [Google Scholar] [CrossRef] [PubMed]
- Melisi, D.; Casalino, S.; Pietrobono, S.; Quinzii, A.; Zecchetto, C.; Merz, V. Integration of liposomal irinotecan in the first-line treatment of metastatic pancreatic cancer: Try to do not think about the white bear. Ther. Adv. Med. Oncol. 2024, 16, 17588359241234487. [Google Scholar] [CrossRef] [PubMed]
- Arneth, B. Tumor Microenvironment. Medicina 2019, 56, 15. [Google Scholar] [CrossRef] [PubMed]
- Ho, W.J.; Jaffee, E.M.; Zheng, L. The tumour microenvironment in pancreatic cancer—clinical challenges and opportunities. Nat. Rev. Clin. Oncol. 2020, 17, 527–540. [Google Scholar] [CrossRef] [PubMed]
- Foster, D.S.; Jones, R.E.; Ransom, R.C.; Longaker, M.T.; Norton, J.A. The evolving relationship of wound healing and tumor stroma. JCI Insight 2018, 3, e99911. [Google Scholar] [CrossRef] [PubMed]
- Velez-Delgado, A.; Donahue, K.L.; Brown, K.L.; Du, W.; Irizarry-Negron, V.; Menjivar, R.E.; Lasse Opsahl, E.L.; Steele, N.G.; The, S.; Lazarus, J.; et al. Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast Reprogramming. Cell Mol. Gastroenterol. Hepatol. 2022, 13, 1673–1699. [Google Scholar] [CrossRef] [PubMed]
- Ren, B.; Cui, M.; Yang, G.; Wang, H.; Feng, M.; You, L.; Zhao, Y. Tumor microenvironment participates in metastasis of pancreatic cancer. Mol. Cancer 2018, 17, 108. [Google Scholar] [CrossRef] [PubMed]
- Wang, S.; Zheng, Y.; Yang, F.; Zhu, L.; Zhu, X.Q.; Wang, Z.F.; Wu, X.L.; Zhou, C.H.; Yan, J.Y.; Hu, B.Y.; et al. The molecular biology of pancreatic adenocarcinoma: Translational challenges and clinical perspectives. Signal Transduct. Target. Ther. 2021, 6, 249. [Google Scholar] [CrossRef] [PubMed]
- Vonlaufen, A.; Joshi, S.; Qu, C.; Phillips, P.A.; Xu, Z.; Parker, N.R.; Toi, C.S.; Pirola, R.C.; Wilson, J.S.; Goldstein, D.; et al. Pancreatic stellate cells: Partners in crime with pancreatic cancer cells. Cancer Res. 2008, 68, 2085–2093. [Google Scholar] [CrossRef] [PubMed]
- Torphy, R.J.; Wang, Z.; True-Yasaki, A.; Volmar, K.E.; Rashid, N.; Yeh, B.; Anderson, J.M.; Johansen, J.S.; Hollingsworth, M.A.; Yeh, J.J.; et al. Stromal Content Is Correlated With Tissue Site, Contrast Retention, and Survival in Pancreatic Adenocarcinoma. JCO Precis. Oncol. 2018, 2, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Bonnans, C.; Chou, J.; Werb, Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 2014, 15, 786–801. [Google Scholar] [CrossRef]
- Hosein, A.N.; Brekken, R.A.; Maitra, A. Pancreatic cancer stroma: An update on therapeutic targeting strategies. Nat. Rev. Gastroenterol. Hepatol. 2020, 17, 487–505. [Google Scholar] [CrossRef]
- Whatcott, C.J.; Diep, C.H.; Jiang, P.; Watanabe, A.; LoBello, J.; Sima, C.; Hostetter, G.; Shepard, H.M.; Von Hoff, D.D.; Han, H. Desmoplasia in Primary Tumors and Metastatic Lesions of Pancreatic Cancer. Clin. Cancer Res. 2015, 21, 3561–3568. [Google Scholar] [CrossRef] [PubMed]
- Bachem, M.G.; Schunemann, M.; Ramadani, M.; Siech, M.; Beger, H.; Buck, A.; Zhou, S.; Schmid-Kotsas, A.; Adler, G. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 2005, 128, 907–921. [Google Scholar] [CrossRef] [PubMed]
- Laklai, H.; Miroshnikova, Y.A.; Pickup, M.W.; Collisson, E.A.; Kim, G.E.; Barrett, A.S.; Hill, R.C.; Lakins, J.N.; Schlaepfer, D.D.; Mouw, J.K.; et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 2016, 22, 497–505. [Google Scholar] [CrossRef]
- Omary, M.B.; Lugea, A.; Lowe, A.W.; Pandol, S.J. The pancreatic stellate cell: A star on the rise in pancreatic diseases. J. Clin. Investig. 2007, 117, 50–59. [Google Scholar] [CrossRef] [PubMed]
- Fu, Y.; Liu, S.; Zeng, S.; Shen, H. The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma. Mol. Cancer 2018, 17, 62. [Google Scholar] [CrossRef]
- Lauth, M.; Bergstrom, A.; Shimokawa, T.; Tostar, U.; Jin, Q.; Fendrich, V.; Guerra, C.; Barbacid, M.; Toftgard, R. DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS. Nat. Struct. Mol. Biol. 2010, 17, 718–725. [Google Scholar] [CrossRef]
- Nakashima, H.; Nakamura, M.; Yamaguchi, H.; Yamanaka, N.; Akiyoshi, T.; Koga, K.; Yamaguchi, K.; Tsuneyoshi, M.; Tanaka, M.; Katano, M. Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer. Cancer Res. 2006, 66, 7041–7049. [Google Scholar] [CrossRef]
- Ene-Obong, A.; Clear, A.J.; Watt, J.; Wang, J.; Fatah, R.; Riches, J.C.; Marshall, J.F.; Chin-Aleong, J.; Chelala, C.; Gribben, J.G.; et al. Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 2013, 145, 1121–1132. [Google Scholar] [CrossRef]
- Tang, D.; Yuan, Z.; Xue, X.; Lu, Z.; Zhang, Y.; Wang, H.; Chen, M.; An, Y.; Wei, J.; Zhu, Y.; et al. High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer. Int. J. Cancer 2012, 130, 2337–2348. [Google Scholar] [CrossRef] [PubMed]
- Mace, T.A.; Ameen, Z.; Collins, A.; Wojcik, S.; Mair, M.; Young, G.S.; Fuchs, J.R.; Eubank, T.D.; Frankel, W.L.; Bekaii-Saab, T.; et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res. 2013, 73, 3007–3018. [Google Scholar] [CrossRef] [PubMed]
- Wu, Q.; Tian, Y.; Zhang, J.; Zhang, H.; Gu, F.; Lu, Y.; Zou, S.; Chen, Y.; Sun, P.; Xu, M.; et al. Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma. Oncotarget 2017, 8, 102721–102738. [Google Scholar] [CrossRef] [PubMed]
- Ferdek, P.E.; Jakubowska, M.A. Biology of pancreatic stellate cells-more than just pancreatic cancer. Pflügers Arch. 2017, 469, 1039–1050. [Google Scholar] [CrossRef] [PubMed]
- Sherman, M.H. Stellate Cells in Tissue Repair, Inflammation, and Cancer. Annu. Rev. Cell Dev. Biol. 2018, 34, 333–355. [Google Scholar] [CrossRef] [PubMed]
- Provenzano, P.P.; Cuevas, C.; Chang, A.E.; Goel, V.K.; Von Hoff, D.D.; Hingorani, S.R. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012, 21, 418–429. [Google Scholar] [CrossRef] [PubMed]
- Bulle, A.; Lim, K.H. Beyond just a tight fortress: Contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer. Signal Transduct. Target. Ther. 2020, 5, 249. [Google Scholar] [CrossRef] [PubMed]
- Linares, J.; Marin-Jimenez, J.A.; Badia-Ramentol, J.; Calon, A. Determinants and Functions of CAFs Secretome During Cancer Progression and Therapy. Front. Cell Dev. Biol. 2020, 8, 621070. [Google Scholar] [CrossRef] [PubMed]
- Sunami, Y.; Haussler, J.; Kleeff, J. Cellular Heterogeneity of Pancreatic Stellate Cells, Mesenchymal Stem Cells, and Cancer-Associated Fibroblasts in Pancreatic Cancer. Cancers 2020, 12, 3770. [Google Scholar] [CrossRef] [PubMed]
- Storz, P. Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 2017, 14, 296–304. [Google Scholar] [CrossRef] [PubMed]
- Hwang, R.F.; Moore, T.T.; Hattersley, M.M.; Scarpitti, M.; Yang, B.; Devereaux, E.; Ramachandran, V.; Arumugam, T.; Ji, B.; Logsdon, C.D.; et al. Inhibition of the hedgehog pathway targets the tumor-associated stroma in pancreatic cancer. Mol. Cancer Res. 2012, 10, 1147–1157. [Google Scholar] [CrossRef] [PubMed]
- Rhim, A.D.; Oberstein, P.E.; Thomas, D.H.; Mirek, E.T.; Palermo, C.F.; Sastra, S.A.; Dekleva, E.N.; Saunders, T.; Becerra, C.P.; Tattersall, I.W.; et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 2014, 25, 735–747. [Google Scholar] [CrossRef] [PubMed]
- Hutton, C.; Heider, F.; Blanco-Gomez, A.; Banyard, A.; Kononov, A.; Zhang, X.; Karim, S.; Paulus-Hock, V.; Watt, D.; Steele, N.; et al. Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity. Cancer Cell 2021, 39, 1227–1244.e20. [Google Scholar] [CrossRef] [PubMed]
- Ohlund, D.; Handly-Santana, A.; Biffi, G.; Elyada, E.; Almeida, A.S.; Ponz-Sarvise, M.; Corbo, V.; Oni, T.E.; Hearn, S.A.; Lee, E.J.; et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 2017, 214, 579–596. [Google Scholar] [CrossRef] [PubMed]
- Elyada, E.; Bolisetty, M.; Laise, P.; Flynn, W.F.; Courtois, E.T.; Burkhart, R.A.; Teinor, J.A.; Belleau, P.; Biffi, G.; Lucito, M.S.; et al. Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts. Cancer Discov. 2019, 9, 1102–1123. [Google Scholar] [CrossRef] [PubMed]
- 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.; et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl. Acad. Sci. USA 2013, 110, 20212–20217. [Google Scholar] [CrossRef] [PubMed]
- Grunwald, B.T.; Devisme, A.; Andrieux, G.; Vyas, F.; Aliar, K.; McCloskey, C.W.; Macklin, A.; Jang, G.H.; Denroche, R.; Romero, J.M.; et al. Spatially confined sub-tumor microenvironments in pancreatic cancer. Cell 2021, 184, 5577–5592.e18. [Google Scholar] [CrossRef] [PubMed]
- Vennin, C.; Melenec, P.; Rouet, R.; Nobis, M.; Cazet, A.S.; Murphy, K.J.; Herrmann, D.; Reed, D.A.; Lucas, M.C.; Warren, S.C.; et al. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan. Nat. Commun. 2019, 10, 3637. [Google Scholar] [CrossRef] [PubMed]
- Kaneda, M.M.; Cappello, P.; Nguyen, A.V.; Ralainirina, N.; Hardamon, C.R.; Foubert, P.; Schmid, M.C.; Sun, P.; Mose, E.; Bouvet, M.; et al. Macrophage PI3Kgamma Drives Pancreatic Ductal Adenocarcinoma Progression. Cancer Discov. 2016, 6, 870–885. [Google Scholar] [CrossRef] [PubMed]
- Daley, D.; Mani, V.R.; Mohan, N.; Akkad, N.; Ochi, A.; Heindel, D.W.; Lee, K.B.; Zambirinis, C.P.; Pandian, G.S.B.; Savadkar, S.; et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat. Med. 2017, 23, 556–567. [Google Scholar] [CrossRef] [PubMed]
- Hao, N.B.; Lu, M.H.; Fan, Y.H.; Cao, Y.L.; Zhang, Z.R.; Yang, S.M. Macrophages in tumor microenvironments and the progression of tumors. Clin. Dev. Immunol. 2012, 2012, 948098. [Google Scholar] [CrossRef] [PubMed]
- Rodriguez, P.C.; Quiceno, D.G.; Zabaleta, J.; Ortiz, B.; Zea, A.H.; Piazuelo, M.B.; Delgado, A.; Correa, P.; Brayer, J.; Sotomayor, E.M.; et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 2004, 64, 5839–5849. [Google Scholar] [CrossRef]
- Xiao, Y.; Yu, D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol. Ther. 2021, 221, 107753. [Google Scholar] [CrossRef] [PubMed]
- Huang, S.; Van Arsdall, M.; Tedjarati, S.; McCarty, M.; Wu, W.; Langley, R.; Fidler, I.J. Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. J. Natl. Cancer Inst. 2002, 94, 1134–1142. [Google Scholar] [CrossRef] [PubMed]
- Lesina, M.; Kurkowski, M.U.; Ludes, K.; Rose-John, S.; Treiber, M.; Kloppel, G.; Yoshimura, A.; Reindl, W.; Sipos, B.; Akira, S.; et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011, 19, 456–469. [Google Scholar] [CrossRef]
- Reid, M.D.; Basturk, O.; Thirabanjasak, D.; Hruban, R.H.; Klimstra, D.S.; Bagci, P.; Altinel, D.; Adsay, V. Tumor-infiltrating neutrophils in pancreatic neoplasia. Mod. Pathol. 2011, 24, 1612–1619. [Google Scholar] [CrossRef]
- Di Federico, A.; Mosca, M.; Pagani, R.; Carloni, R.; Frega, G.; De Giglio, A.; Rizzo, A.; Ricci, D.; Tavolari, S.; Di Marco, M.; et al. Immunotherapy in Pancreatic Cancer: Why Do We Keep Failing? A Focus on Tumor Immune Microenvironment, Predictive Biomarkers and Treatment Outcomes. Cancers 2022, 14, 2429. [Google Scholar] [CrossRef]
- Hartupee, C.; Nagalo, B.M.; Chabu, C.Y.; Tesfay, M.Z.; Coleman-Barnett, J.; West, J.T.; Moaven, O. Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target. Front. Immunol. 2024, 15, 1287459. [Google Scholar] [CrossRef]
- Porembka, M.R.; Mitchem, J.B.; Belt, B.A.; Hsieh, C.S.; Lee, H.M.; Herndon, J.; Gillanders, W.E.; Linehan, D.C.; Goedegebuure, P. Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol. Immunother. 2012, 61, 1373–1385. [Google Scholar] [CrossRef]
- Pinton, L.; Solito, S.; Damuzzo, V.; Francescato, S.; Pozzuoli, A.; Berizzi, A.; Mocellin, S.; Rossi, C.R.; Bronte, V.; Mandruzzato, S. Activated T cells sustain myeloid-derived suppressor cell-mediated immune suppression. Oncotarget 2016, 7, 1168–1184. [Google Scholar] [CrossRef]
- Nagaraj, S.; Gabrilovich, D.I. Regulation of suppressive function of myeloid-derived suppressor cells by CD4+ T cells. Semin. Cancer Biol. 2012, 22, 282–288. [Google Scholar] [CrossRef] [PubMed]
- Peterson, R.A. Regulatory T-cells: Diverse phenotypes integral to immune homeostasis and suppression. Toxicol. Pathol. 2012, 40, 186–204. [Google Scholar] [CrossRef] [PubMed]
- Hou, P.; Kapoor, A.; Zhang, Q.; Li, J.; Wu, C.J.; Li, J.; Lan, Z.; Tang, M.; Ma, X.; Ackroyd, J.J.; et al. Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer. Cancer Discov. 2020, 10, 1058–1077. [Google Scholar] [CrossRef] [PubMed]
- Pandiyan, P.; Zheng, L.; Ishihara, S.; Reed, J.; Lenardo, M.J. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat. Immunol. 2007, 8, 1353–1362. [Google Scholar] [CrossRef] [PubMed]
- Beyer, K.; Normann, L.; Sendler, M.; Kading, A.; Heidecke, C.D.; Partecke, L.I.; von Bernstorff, W. TRAIL Promotes Tumor Growth in a Syngeneic Murine Orthotopic Pancreatic Cancer Model and Affects the Host Immune Response. Pancreas 2016, 45, 401–408. [Google Scholar] [CrossRef] [PubMed]
- Carstens, J.L.; Correa de Sampaio, P.; Yang, D.; Barua, S.; Wang, H.; Rao, A.; Allison, J.P.; LeBleu, V.S.; Kalluri, R. Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nat. Commun. 2017, 8, 15095. [Google Scholar] [CrossRef] [PubMed]
- Katsuta, E.; Qi, Q.; Peng, X.; Hochwald, S.N.; Yan, L.; Takabe, K. Pancreatic adenocarcinomas with mature blood vessels have better overall survival. Sci. Rep. 2019, 9, 1310. [Google Scholar] [CrossRef] [PubMed]
- Erkan, M.; Kurtoglu, M.; Kleeff, J. The role of hypoxia in pancreatic cancer: A potential therapeutic target? Expert. Rev. Gastroenterol. Hepatol. 2016, 10, 301–316. [Google Scholar] [CrossRef] [PubMed]
- Yamamoto, K.; Venida, A.; Yano, J.; Biancur, D.E.; Kakiuchi, M.; Gupta, S.; Sohn, A.S.W.; Mukhopadhyay, S.; Lin, E.Y.; Parker, S.J.; et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature 2020, 581, 100–105. [Google Scholar] [CrossRef] [PubMed]
- Sousa, C.M.; Biancur, D.E.; Wang, X.; Halbrook, C.J.; Sherman, M.H.; Zhang, L.; Kremer, D.; Hwang, R.F.; Witkiewicz, A.K.; Ying, H.; et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 2016, 536, 479–483. [Google Scholar] [CrossRef] [PubMed]
- Schumacher, T.N.; Schreiber, R.D. Neoantigens in cancer immunotherapy. Science 2015, 348, 69–74. [Google Scholar] [CrossRef] [PubMed]
- Bellone, G.; Turletti, A.; Artusio, E.; Mareschi, K.; Carbone, A.; Tibaudi, D.; Robecchi, A.; Emanuelli, G.; Rodeck, U. Tumor-associated transforming growth factor-beta and interleukin-10 contribute to a systemic Th2 immune phenotype in pancreatic carcinoma patients. Am. J. Pathol. 1999, 155, 537–547. [Google Scholar] [CrossRef] [PubMed]
- Beatty, G.L.; Winograd, R.; Evans, R.A.; Long, K.B.; Luque, S.L.; Lee, J.W.; Clendenin, C.; Gladney, W.L.; Knoblock, D.M.; Guirnalda, P.D.; et al. Exclusion of T Cells from Pancreatic Carcinomas in Mice Is Regulated by Ly6C(low) F4/80(+) Extratumoral Macrophages. Gastroenterology 2015, 149, 201–210. [Google Scholar] [CrossRef] [PubMed]
- Wattenberg, M.M.; Herrera, V.M.; Giannone, M.A.; Gladney, W.L.; Carpenter, E.L.; Beatty, G.L. Systemic inflammation is a determinant of outcomes of CD40 agonist-based therapy in pancreatic cancer patients. JCI Insight 2021, 6, e145389. [Google Scholar] [CrossRef] [PubMed]
- Moon, Y.W.; Hajjar, J.; Hwu, P.; Naing, A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J. Immunother. Cancer 2015, 3, 51. [Google Scholar] [CrossRef] [PubMed]
- Winograd, R.; Byrne, K.T.; Evans, R.A.; Odorizzi, P.M.; Meyer, A.R.; Bajor, D.L.; Clendenin, C.; Stanger, B.Z.; Furth, E.E.; Wherry, E.J.; et al. Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma. Cancer Immunol. Res. 2015, 3, 399–411. [Google Scholar] [CrossRef] [PubMed]
- Kitamoto, S.; Yokoyama, S.; Higashi, M.; Yamada, N.; Takao, S.; Yonezawa, S. MUC1 enhances hypoxia-driven angiogenesis through the regulation of multiple proangiogenic factors. Oncogene 2013, 32, 4614–4621. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.; Zhou, W.; Zhong, Y.; Huo, Y.; Fan, P.; Zhan, S.; Xiao, J.; Jin, X.; Gou, S.; Yin, T.; et al. Overexpression of G protein-coupled receptor GPR87 promotes pancreatic cancer aggressiveness and activates NF-kappaB signaling pathway. Mol. Cancer 2017, 16, 61. [Google Scholar] [CrossRef] [PubMed]
- Wei, D.; Le, X.; Zheng, L.; Wang, L.; Frey, J.A.; Gao, A.C.; Peng, Z.; Huang, S.; Xiong, H.Q.; Abbruzzese, J.L.; et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 2003, 22, 319–329. [Google Scholar] [CrossRef] [PubMed]
- Kurahara, H.; Takao, S.; Maemura, K.; Mataki, Y.; Kuwahata, T.; Maeda, K.; Sakoda, M.; Iino, S.; Ishigami, S.; Ueno, S.; et al. M2-polarized tumor-associated macrophage infiltration of regional lymph nodes is associated with nodal lymphangiogenesis and occult nodal involvement in pN0 pancreatic cancer. Pancreas 2013, 42, 155–159. [Google Scholar] [CrossRef] [PubMed]
- Kurahara, H.; Takao, S.; Maemura, K.; Shinchi, H.; Natsugoe, S.; Aikou, T. Impact of vascular endothelial growth factor-C and -D expression in human pancreatic cancer: Its relationship to lymph node metastasis. Clin. Cancer Res. 2004, 10, 8413–8420. [Google Scholar] [CrossRef]
- Ikenaga, N.; Ohuchida, K.; Mizumoto, K.; Cui, L.; Kayashima, T.; Morimatsu, K.; Moriyama, T.; Nakata, K.; Fujita, H.; Tanaka, M. CD10+ pancreatic stellate cells enhance the progression of pancreatic cancer. Gastroenterology 2010, 139, 1041–1051.e8. [Google Scholar] [CrossRef]
- Jiang, Y.; Du, Z.; Yang, F.; Di, Y.; Li, J.; Zhou, Z.; Pillarisetty, V.G.; Fu, D. FOXP3+ lymphocyte density in pancreatic cancer correlates with lymph node metastasis. PLoS ONE 2014, 9, e106741. [Google Scholar] [CrossRef]
- Kurahara, H.; Shinchi, H.; Mataki, Y.; Maemura, K.; Noma, H.; Kubo, F.; Sakoda, M.; Ueno, S.; Natsugoe, S.; Takao, S. Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J. Surg. Res. 2011, 167, e211–e219. [Google Scholar] [CrossRef]
- Tang, D.; Zhang, J.; Yuan, Z.; Zhang, H.; Chong, Y.; Huang, Y.; Wang, J.; Xiong, Q.; Wang, S.; Wu, Q.; et al. PSC-derived Galectin-1 inducing epithelial-mesenchymal transition of pancreatic ductal adenocarcinoma cells by activating the NF-kappaB pathway. Oncotarget 2017, 8, 86488–86502. [Google Scholar] [CrossRef] [PubMed]
- Wu, Y.S.; Chung, I.; Wong, W.F.; Masamune, A.; Sim, M.S.; Looi, C.Y. Paracrine IL-6 signaling mediates the effects of pancreatic stellate cells on epithelial-mesenchymal transition via Stat3/Nrf2 pathway in pancreatic cancer cells. Biochim. Biophys. Acta Gen. Subj. 2017, 1861, 296–306. [Google Scholar] [CrossRef]
- Campbell, A.S.; Albo, D.; Kimsey, T.F.; White, S.L.; Wang, T.N. Macrophage inflammatory protein-3alpha promotes pancreatic cancer cell invasion. J. Surg. Res. 2005, 123, 96–101. [Google Scholar] [CrossRef] [PubMed]
- Goicoechea, S.M.; Garcia-Mata, R.; Staub, J.; Valdivia, A.; Sharek, L.; McCulloch, C.G.; Hwang, R.F.; Urrutia, R.; Yeh, J.J.; Kim, H.J.; et al. Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts. Oncogene 2014, 33, 1265–1273. [Google Scholar] [CrossRef] [PubMed]
- Onishi, H.; Kai, M.; Odate, S.; Iwasaki, H.; Morifuji, Y.; Ogino, T.; Morisaki, T.; Nakashima, Y.; Katano, M. Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer. Cancer Sci. 2011, 102, 1144–1150. [Google Scholar] [CrossRef]
- Nielsen, S.R.; Quaranta, V.; Linford, A.; Emeagi, P.; Rainer, C.; Santos, A.; Ireland, L.; Sakai, T.; Sakai, K.; Kim, Y.S.; et al. Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat. Cell Biol. 2016, 18, 549–560. [Google Scholar] [CrossRef]
- Eash, K.J.; Greenbaum, A.M.; Gopalan, P.K.; Link, D.C. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J. Clin. Investig. 2010, 120, 2423–2431. [Google Scholar] [CrossRef] [PubMed]
- Ji, T.; Lang, J.; Wang, J.; Cai, R.; Zhang, Y.; Qi, F.; Zhang, L.; Zhao, X.; Wu, W.; Hao, J.; et al. Designing Liposomes To Suppress Extracellular Matrix Expression To Enhance Drug Penetration and Pancreatic Tumor Therapy. ACS Nano 2017, 11, 8668–8678. [Google Scholar] [CrossRef] [PubMed]
- Diop-Frimpong, B.; Chauhan, V.P.; Krane, S.; Boucher, Y.; Jain, R.K. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc. Natl. Acad. Sci. USA 2011, 108, 2909–2914. [Google Scholar] [CrossRef] [PubMed]
- Jiang, H.; Hegde, S.; Knolhoff, B.L.; Zhu, Y.; Herndon, J.M.; Meyer, M.A.; Nywening, T.M.; Hawkins, W.G.; Shapiro, I.M.; Weaver, D.T.; et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med. 2016, 22, 851–860. [Google Scholar] [CrossRef] [PubMed]
- Gunderson, A.J.; Yamazaki, T.; McCarty, K.; Phillips, M.; Alice, A.; Bambina, S.; Zebertavage, L.; Friedman, D.; Cottam, B.; Newell, P.; et al. Blockade of fibroblast activation protein in combination with radiation treatment in murine models of pancreatic adenocarcinoma. PLoS ONE 2019, 14, e0211117. [Google Scholar] [CrossRef] [PubMed]
- Kakarla, S.; Chow, K.K.; Mata, M.; Shaffer, D.R.; Song, X.T.; Wu, M.F.; Liu, H.; Wang, L.L.; Rowley, D.R.; Pfizenmaier, K.; et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol. Ther. 2013, 21, 1611–1620. [Google Scholar] [CrossRef] [PubMed]
- Lo, A.; Wang, L.S.; Scholler, J.; Monslow, J.; Avery, D.; Newick, K.; O’Brien, S.; Evans, R.A.; Bajor, D.J.; Clendenin, C.; et al. Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells. Cancer Res. 2015, 75, 2800–2810. [Google Scholar] [CrossRef] [PubMed]
- Aguilera, K.Y.; Huang, H.; Du, W.; Hagopian, M.M.; Wang, Z.; Hinz, S.; Hwang, T.H.; Wang, H.; Fleming, J.B.; Castrillon, D.H.; et al. Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma. Mol. Cancer Ther. 2017, 16, 2473–2485. [Google Scholar] [CrossRef] [PubMed]
- Sodir, N.M.; Swigart, L.B.; Karnezis, A.N.; Hanahan, D.; Evan, G.I.; Soucek, L. Endogenous Myc maintains the tumor microenvironment. Genes Dev. 2011, 25, 907–916. [Google Scholar] [CrossRef] [PubMed]
- Byrne, K.T.; Betts, C.B.; Mick, R.; Sivagnanam, S.; Bajor, D.L.; Laheru, D.A.; Chiorean, E.G.; O’Hara, M.H.; Liudahl, S.M.; Newcomb, C.; et al. Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer. Clin. Cancer Res. 2021, 27, 4574–4586. [Google Scholar] [CrossRef] [PubMed]
- Padron, L.J.; Maurer, D.M.; O’Hara, M.H.; O’Reilly, E.M.; Wolff, R.A.; Wainberg, Z.A.; Ko, A.H.; Fisher, G.; Rahma, O.; Lyman, J.P.; et al. Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: Clinical and immunologic analyses from the randomized phase 2 PRINCE trial. Nat. Med. 2022, 28, 1167–1177. [Google Scholar] [CrossRef] [PubMed]
- Vonderheide, R.H. CD40 Agonist Antibodies in Cancer Immunotherapy. Annu. Rev. Med. 2020, 71, 47–58. [Google Scholar] [CrossRef] [PubMed]
- Zhou, W.; Zhou, Y.; Chen, X.; Ning, T.; Chen, H.; Guo, Q.; Zhang, Y.; Liu, P.; Zhang, Y.; Li, C.; et al. Pancreatic cancer-targeting exosomes for enhancing immunotherapy and reprogramming tumor microenvironment. Biomaterials 2021, 268, 120546. [Google Scholar] [CrossRef] [PubMed]
- Lutz, E.R.; Wu, A.A.; Bigelow, E.; Sharma, R.; Mo, G.; Soares, K.; Solt, S.; Dorman, A.; Wamwea, A.; Yager, A.; et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol. Res. 2014, 2, 616–631. [Google Scholar] [CrossRef] [PubMed]
- Ries, C.H.; Cannarile, M.A.; Hoves, S.; Benz, J.; Wartha, K.; Runza, V.; Rey-Giraud, F.; Pradel, L.P.; Feuerhake, F.; Klaman, I.; et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 2014, 25, 846–859. [Google Scholar] [CrossRef] [PubMed]
- Zhu, Y.; Knolhoff, B.L.; Meyer, M.A.; Nywening, T.M.; West, B.L.; Luo, J.; Wang-Gillam, A.; Goedegebuure, S.P.; Linehan, D.C.; DeNardo, D.G. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014, 74, 5057–5069. [Google Scholar] [CrossRef] [PubMed]
- Noel, M.; O’Reilly, E.M.; Wolpin, B.M.; Ryan, D.P.; Bullock, A.J.; Britten, C.D.; Linehan, D.C.; Belt, B.A.; Gamelin, E.C.; Ganguly, B.; et al. Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma. Investig. New Drugs 2020, 38, 800–811. [Google Scholar] [CrossRef] [PubMed]
- Sherman, M.H.; Beatty, G.L. Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance. Annu. Rev. Pathol. 2023, 18, 123–148. [Google Scholar] [CrossRef] [PubMed]
- Nywening, T.M.; Belt, B.A.; Cullinan, D.R.; Panni, R.Z.; Han, B.J.; Sanford, D.E.; Jacobs, R.C.; Ye, J.; Patel, A.A.; Gillanders, W.E.; et al. Targeting both tumour-associated CXCR2(+) neutrophils and CCR2(+) macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut 2018, 67, 1112–1123. [Google Scholar] [CrossRef] [PubMed]
- Hegde, S.; Krisnawan, V.E.; Herzog, B.H.; Zuo, C.; Breden, M.A.; Knolhoff, B.L.; Hogg, G.D.; Tang, J.P.; Baer, J.M.; Mpoy, C.; et al. Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer. Cancer Cell 2020, 37, 289–307.e9. [Google Scholar] [CrossRef] [PubMed]
- Byrne, K.T.; Vonderheide, R.H. CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer. Cell Rep. 2016, 15, 2719–2732. [Google Scholar] [CrossRef] [PubMed]
- Lin, J.H.; Huffman, A.P.; Wattenberg, M.M.; Walter, D.M.; Carpenter, E.L.; Feldser, D.M.; Beatty, G.L.; Furth, E.E.; Vonderheide, R.H. Type 1 conventional dendritic cells are systemically dysregulated early in pancreatic carcinogenesis. J. Exp. Med. 2020, 217, e20190673. [Google Scholar] [CrossRef] [PubMed]
- Dalin, S.; Sullivan, M.R.; Lau, A.N.; Grauman-Boss, B.; Mueller, H.S.; Kreidl, E.; Fenoglio, S.; Luengo, A.; Lees, J.A.; Vander Heiden, M.G.; et al. Deoxycytidine Release from Pancreatic Stellate Cells Promotes Gemcitabine Resistance. Cancer Res. 2019, 79, 5723–5733. [Google Scholar] [CrossRef] [PubMed]
- Van de Velde, L.A.; Subramanian, C.; Smith, A.M.; Barron, L.; Qualls, J.E.; Neale, G.; Alfonso-Pecchio, A.; Jackowski, S.; Rock, C.O.; Wynn, T.A.; et al. T Cells Encountering Myeloid Cells Programmed for Amino Acid-dependent Immunosuppression Use Rictor/mTORC2 Protein for Proliferative Checkpoint Decisions. J. Biol. Chem. 2017, 292, 15–30. [Google Scholar] [CrossRef] [PubMed]
- Long, K.B.; Gladney, W.L.; Tooker, G.M.; Graham, K.; Fraietta, J.A.; Beatty, G.L. IFNgamma and CCL2 Cooperate to Redirect Tumor-Infiltrating Monocytes to Degrade Fibrosis and Enhance Chemotherapy Efficacy in Pancreatic Carcinoma. Cancer Discov. 2016, 6, 400–413. [Google Scholar] [CrossRef] [PubMed]
- Leone, R.D.; Zhao, L.; Englert, J.M.; Sun, I.M.; Oh, M.H.; Sun, I.H.; Arwood, M.L.; Bettencourt, I.A.; Patel, C.H.; Wen, J.; et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 2019, 366, 1013–1021. [Google Scholar] [CrossRef] [PubMed]
- Olivares, O.; Mayers, J.R.; Gouirand, V.; Torrence, M.E.; Gicquel, T.; Borge, L.; Lac, S.; Roques, J.; Lavaut, M.N.; Berthezene, P.; et al. Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat. Commun. 2017, 8, 16031. [Google Scholar] [CrossRef] [PubMed]
- Wu, Y.; Han, W.; Dong, H.; Liu, X.; Su, X. The rising roles of exosomes in the tumor microenvironment reprogramming and cancer immunotherapy. MedComm 2024, 5, e541. [Google Scholar] [CrossRef] [PubMed]
- Adem, B.; Bastos, N.; Ruivo, C.F.; Sousa-Alves, S.; Dias, C.; Vieira, P.F.; Batista, I.A.; Cavadas, B.; Saur, D.; Machado, J.C.; et al. Exosomes define a local and systemic communication network in healthy pancreas and pancreatic ductal adenocarcinoma. Nat. Commun. 2024, 15, 1496. [Google Scholar] [CrossRef] [PubMed]
- Chen, Y.; Kleeff, J.; Sunami, Y. Pancreatic cancer cell- and cancer-associated fibroblast-derived exosomes in disease progression, metastasis, and therapy. Discov. Oncol. 2024, 15, 253. [Google Scholar] [CrossRef]
- Kimbara, S.; Kondo, S. Immune checkpoint and inflammation as therapeutic targets in pancreatic carcinoma. World J. Gastroenterol. 2016, 22, 7440–7452. [Google Scholar] [CrossRef]
- Gilles, M.E.; Maione, F.; Cossutta, M.; Carpentier, G.; Caruana, L.; Di Maria, S.; Houppe, C.; Destouches, D.; Shchors, K.; Prochasson, C.; et al. Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature. Cancer Res. 2016, 76, 7181–7193. [Google Scholar] [CrossRef] [PubMed]
- Huang, Y.; Yuan, J.; Righi, E.; Kamoun, W.S.; Ancukiewicz, M.; Nezivar, J.; Santosuosso, M.; Martin, J.D.; Martin, M.R.; Vianello, F.; et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc. Natl. Acad. Sci. USA 2012, 109, 17561–17566. [Google Scholar] [CrossRef]
- Tien, Y.W.; Wu, Y.M.; Lin, W.C.; Lee, H.S.; Lee, P.H. Pancreatic carcinoma cells stimulate proliferation and matrix synthesis of hepatic stellate cells. J. Hepatol. 2009, 51, 307–314. [Google Scholar] [CrossRef] [PubMed]
- Steele, C.W.; Karim, S.A.; Leach, J.D.G.; Bailey, P.; Upstill-Goddard, R.; Rishi, L.; Foth, M.; Bryson, S.; McDaid, K.; Wilson, Z.; et al. CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. Cancer Cell 2016, 29, 832–845. [Google Scholar] [CrossRef]
- Banh, R.S.; Biancur, D.E.; Yamamoto, K.; Sohn, A.S.W.; Walters, B.; Kuljanin, M.; Gikandi, A.; Wang, H.; Mancias, J.D.; Schneider, R.J.; et al. Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer. Cell 2020, 183, 1202–1218.e25. [Google Scholar] [CrossRef]
- Renz, B.W.; Takahashi, R.; Tanaka, T.; Macchini, M.; Hayakawa, Y.; Dantes, Z.; Maurer, H.C.; Chen, X.; Jiang, Z.; Westphalen, C.B.; et al. β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer. Cancer Cell 2018, 33, 75–90.e7. [Google Scholar] [CrossRef]
- Saloman, J.L.; Albers, K.M.; Li, D.; Hartman, D.J.; Crawford, H.C.; Muha, E.A.; Rhim, A.D.; Davis, B.M. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc. Natl. Acad. Sci. USA 2016, 113, 3078–3083. [Google Scholar] [CrossRef]
- Riquelme, E.; Zhang, Y.; Zhang, L.; Montiel, M.; Zoltan, M.; Dong, W.; Quesada, P.; Sahin, I.; Chandra, V.; San Lucas, A.; et al. Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes. Cell 2019, 178, 795–806.e12. [Google Scholar] [CrossRef] [PubMed]
- Gopalakrishnan, V.; Spencer, C.N.; Nezi, L.; Reuben, A.; Andrews, M.C.; Karpinets, T.V.; Prieto, P.A.; Vicente, D.; Hoffman, K.; Wei, S.C.; et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018, 359, 97–103. [Google Scholar] [CrossRef]
- Matson, V.; Fessler, J.; Bao, R.; Chongsuwat, T.; Zha, Y.; Alegre, M.L.; Luke, J.J.; Gajewski, T.F. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018, 359, 104–108. [Google Scholar] [CrossRef] [PubMed]
- de Castilhos, J.; Tillmanns, K.; Blessing, J.; Larano, A.; Borisov, V.; Stein-Thoeringer, C.K. Microbiome and pancreatic cancer: Time to think about chemotherapy. Gut Microbes 2024, 16, 2374596. [Google Scholar] [CrossRef] [PubMed]
- Mirji, G.; Worth, A.; Bhat, S.A.; El Sayed, M.; Kannan, T.; Goldman, A.R.; Tang, H.Y.; Liu, Q.; Auslander, N.; Dang, C.V.; et al. The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer. Sci. Immunol. 2022, 7, eabn0704. [Google Scholar] [CrossRef] [PubMed]
- Tintelnot, J.; Xu, Y.; Lesker, T.R.; Schonlein, M.; Konczalla, L.; Giannou, A.D.; Pelczar, P.; Kylies, D.; Puelles, V.G.; Bielecka, A.A.; et al. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature 2023, 615, 168–174. [Google Scholar] [CrossRef] [PubMed]
- Kartal, E.; Schmidt, T.S.B.; Molina-Montes, E.; Rodriguez-Perales, S.; Wirbel, J.; Maistrenko, O.M.; Akanni, W.A.; Alashkar Alhamwe, B.; Alves, R.J.; Carrato, A.; et al. A faecal microbiota signature with high specificity for pancreatic cancer. Gut 2022, 71, 1359–1372. [Google Scholar] [CrossRef] [PubMed]
Title of the Trial | Trial Number |
---|---|
Study Assessing Safety and Efficacy of Combination of BL-8040 and Pembrolizumab in Metastatic Pancreatic Cancer Patients (COMBAT/KEYNOTE-202) (COMBAT) | NCT02826486 |
Olaptesed (NOX-A12) Alone and in Combination with Pembrolizumab in Colorectal and Pancreatic Cancer (Keynote-559) | NCT03168139 |
Defactinib Combined with Pembrolizumab and Gemcitabine in Patients with Advanced Cancer | NCT02546531 |
Study of Pembrolizumab with or without Defactinib Following Chemotherapy as a Neoadjuvant and Adjuvant Treatment for Resectable Pancreatic Ductal Adenocarcinoma | NCT03727880 |
Losartan and Hypofractionated Rx After Chemo for Tx of Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer (SHAPER) | NCT04106856 |
A Pilot, Prospective, Non-randomized Evaluation of the Safety of Anakinra Plus Standard Chemotherapy | NCT02021422 |
First-in-human Study of Oral TP-0903 (a Novel Inhibitor of AXL Kinase) in Patients with Advanced Solid Tumors | NCT02729298 |
Combination Therapy for Patients with Untreated Metastatic Pancreatic Ductal Adenocarcinoma | NCT02754726 |
Stromal TARgeting for PAncreatic Cancer (STAR_PAC) | NCT03307148 |
Danvatirsen and Durvalumab in Treating Patients with Advanced and Refractory Pancreatic, Non-Small Cell Lung Cancer, and Mismatch Repair Deficient Colorectal Cancer | NCT02983578 |
Category | Target Strategy | Mechanism | References |
---|---|---|---|
Epithelial-to-Mesenchymal Transition (EMT) | IL-6/STAT3, galectin-1, Nrf2, MIP-3α, MMP9, palladin, HIF1, SHH, HGF, periostin, granulin, CXCR2 pathway | These molecules and pathways are linked to the promotion of EMT, enhancing the invasion and migration abilities of pancreatic cancer cells within the TME | [145,146,147,148,149,150,151] |
Targeting fibrosis in TME | Pirfenidone, Losartan, FAK inhibitors (Defactinib), PD-L1 antibodies (Pembrolizumab), CXCR4 inhibitors (NOX-A12 and BL-8040), CARs targeting FAP, DDR1 inhibitors, VDR modulation, ATRA*, Fasudil | Targeting stromal components such as CAFs, fibrosis, and ECM remodeling, using various inhibitors and drugs, to enhance drug delivery, reduce fibrosis, and improve therapeutic outcomes | [82,152,153,154,155,156,157,158] |
Targeting TME immune cells | CSF1R inhibitors (Cabiralizumab), PD1 checkpoint inhibitor (nivolumab), Myc blockers CD40 agonists, galectin-9 blockade, T-reg elimination, CCR2 and CXCR2 inhibitors, dendritic cell boosting, glutamine antagonists, PRODH1 inhibition | Strategies focus on modulating immune cells within the TME, enhancing anti-tumor immune responses, and improving therapy sensitivity through various pathways and inhibitors | [14,74,82,134,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177] |
Targeting exosomes in the TME | Communication via exosomes between PDAC cells and cells of the TME (e.g., disruption of the galectin-9/dectin 1 axis) | Strategies focusing on exploiting the cargo of exosomes against angiogenesis and in favor of tumor efficacy | [163,178,179,180] |
Other precision TME targeting strategies | PD-1/PD-L1 and CTLA-4 inhibition (Pembrolizumab, Nivolumab, and Ipilimumab), VEGF/VEGFR2 blockade (SEMA3A), premetastatic niche targeting (PDGF, TGFβ1, and FGF2, antibodies or Ly6G+ or CXCR2 diminishing), IL-1R/IRAK4 inhibition, AXL inhibition (TP-0903), bacterial signatures (TMAO, 3-IAA), targeting microbiota | Broad approaches targeting angiogenesis, immune checkpoint pathways, the premetastatic niche, and other factors within the TME to improve the effectiveness of pancreatic cancer treatments | [77,106,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Vitorakis, N.; Gargalionis, A.N.; Papavassiliou, K.A.; Adamopoulos, C.; Papavassiliou, A.G. Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment. Cancers 2024, 16, 2876. https://doi.org/10.3390/cancers16162876
Vitorakis N, Gargalionis AN, Papavassiliou KA, Adamopoulos C, Papavassiliou AG. Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment. Cancers. 2024; 16(16):2876. https://doi.org/10.3390/cancers16162876
Chicago/Turabian StyleVitorakis, Nikolaos, Antonios N. Gargalionis, Kostas A. Papavassiliou, Christos Adamopoulos, and Athanasios G. Papavassiliou. 2024. "Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment" Cancers 16, no. 16: 2876. https://doi.org/10.3390/cancers16162876