Tumorigenesis and Tumor Microenvironment in Pancreatic Cancer: Comparison
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Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide. Unfortunately, therapeutic gains in the treatment of other cancers have not successfully translated to pancreatic cancer treatments. Management of pancreatic cancer is difficult due to the lack of effective therapies and the rapid development of drug resistance. In addition, various cell types in the tumor microenvironment exert immunosuppressive effects that worsen prognosis.

  • advanced pancreatic cancer
  • tumor microenvironment
  • stromal depletion
  • immune modulation

1. Introduction

Pancreatic cancer accounts for 6–8% of annual cancer-related mortalities [1]. The mortality and incidence rates are nearly the same due to the heterogeneous nature of pancreatic cancer, which equates to a poor prognosis in most patients [2]. Despite the robust growth in basic research on pancreatic cancer and improvements in surgical techniques, the 5-year survival rate for patients remains relatively low at approximately 8–9 per 100,000, which is lower than the survival rates for most other cancers [3].
The obstacles in managing pancreatic cancer are multidimensional. Pancreatic cancer is a heterogeneous array of pathological and molecular conditions rather than a singular disease, which leads different patients to respond differently to the same treatment [4,5][4][5]. The lack of accurate, cost-effective screening strategies makes pancreatic cancer more difficult to diagnose early than breast, colorectal, and lung cancers [6]. Most patients with early-stage, localized pancreatic cancer present no symptoms or only mild, non-specific symptoms such as fatigue, epigastric discomfort, and loss of appetite. Progressive abdominal pain, weight loss, and jaundice are usually the symptoms that finally raise the alarm for patients and healthcare providers, but by this point, the disease has typically reached an advanced stage that is difficult to treat. By the time of diagnosis, only 20–30% of patients are eligible for surgical resection, and up to 50% may already be at an unresectable metastatic stage [7]. Even for the small subset of patients who can undergo surgical resection, the 5-year survival rate remains lower than 20% [8]. Distal metastasis occurs early during pancreatic cancer progression [9], and metastatic pancreatic cancer is associated with a mortality rate of 95% and median overall survival shorter than one year [9].
The traditional first-line treatment for patients with unresectable pancreatic cancer is the classical chemotherapy gemcitabine. However, many patients develop resistance to this drug within weeks of treatment initiation [10]. Whereas multiple forms of chemotherapy or targeted therapies are available for other cancers, treatment options for pancreatic cancer are severely limited.
Successful cancer management is based on a comprehensive molecular and cytological understanding of tumor cells. Technological innovation in biomedical research has profoundly enriched ourthe knowledge about pancreatic tumorigenesis and progression over the last decade [6,11][6][11]. However, a series of promising drug targets have been discovered and may fill gaps in the treatment of advanced pancreatic cancer and enable individualized cancer therapy.

2. Tumorigenesis and Tumor Microenvironment in Pancreatic Cancer

2.1. Hallmarks of Pancreatic Cancer

Cancer cells share typical hallmarks that distinguish them from normal cells, and cancers of different origins demonstrate unique characteristics that are potentially targetable [30][12]. Pancreatic cancer cells carry specific genomic alterations critical to tumorigenesis and progression [31][13]. Classically, pancreatic cancer tumorigenesis has been considered the result of a sequential accumulation of molecular perturbations in resident pancreatic acinous cells that lead to intraepithelial neoplasia and, ultimately, cancer [32,33][14][15]. These disturbances include: mutations in KRAS, TP53, CDK4/6, and BRCA1/2; deletion of BRAF; and gene rearrangements of NTRK, ALK, and NRG1 [32,34][14][16]. However, clinical efforts to target various genomic alterations for treatment have so far proved to be disappointing [35][17]. Metabolic reprogramming is another remarkable feature of pancreatic cancer cells [30][12]. The hypoxic intra-tumoral environment leads tumor cells to shift their metabolism from oxidative phosphorylation toward oxygen-independent glycolysis, known as the “Warburg effect” [36[18][19],37], to help tumor cells survive the scarcity of nutrients and oxygen in their microenvironment. As part of this metabolic shift, redundant glycolytic intermediates enter various metabolic bypass pathways [38[20][21],39], and glutamine transportation is hyperactivated [40][22]. Autophagy and macropinocytosis are hyperactivated to scavenge nutrients [41,42,43,44][23][24][25][26]. Novel therapeutic opportunities exist in inhibiting cancer cell mitochondrial bioenergetics or scavenging pathways, as reviewed previously [45][27].

2.2. The Inter-Tumoral Microenvironment of Pancreatic Cancer

In the pancreatic tumor microenvironment, the extracellular matrix (ECM), immune and stromal cells, and secretory signals interact to promote cancer cell invasion, dissemination, and distal colonization [42,46][24][28]. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment create a desmoplastic extracellular matrix that helps drive pancreatic cancer cell progression and drug resistance by secreting various fibrotic substances, such as collagen and hyaluronic acid [47][29]. CAFs also secrete various amino acids and lipids that support cancer cell survival [48,49,50][30][31][32]. There are at least two types of CAFs within the tumor microenvironment. Myofibroblasts are characterized by α-smooth muscle actin (α-SMA), and inflammatory CAFs lose myofibroblastic features and secrete various inflammatory cytokines [51,52][33][34]. Immune cells in the PTME play a critical role during cancer progression. Compared to other types of cancer, most pancreatic cancers, if not all, are immunologically cold, which is represented by the limited infiltration of effector T cells and low expression of PD-L1, thereby eliciting low responses to immune checkpoint inhibitor therapy [53][35]. The restrained proliferation and activation of cytotoxic T cells are closely related to the composition of immune mi, mainly comprising macrophages, myeloid-derived suppressor cells (MDSC), fibroblasts, neutrophils, and T regulatory cells [54,55][36][37]. Tumor-associated macrophages (TAMs) are key components of cancer stroma inflammation, presenting a spectrum of functional states with two opposing extremes [42][24]. While polarized M1 macrophages are pro-inflammatory and anti-neoplastic, M2 macrophages have the opposed phenotype, which promotes tumor growth and predominates during cancer development [42][24]. Multiple lines of evidence have shown that macrophage depletion efficiently impairs angiogenesis and reduces metastasis formation [56][38]. Inhibition of TAMs also alleviates gemcitabine resistance by inactivating CDA, an enzyme critically involved in the inactivation of gemcitabine [57][39]. Myeloid-derived suppressor cells (MDSCs) are strongly increased in both the circulation and the TME of PDAC patients, and a positive correlation exists between the cell count and tumor staging [58][40]. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-1β secreted by tumor cells are critical to the development of MDSCs [59][41]. MDSCs increase the expression of tumor PD-L1 expression via the activation of EGFR/MAPK signaling pathway and result in CD8+ T cell exhaustion and T regulatory cell expansion [58[40][42],60], thus abrogation of tumor-derived GM-CSF secretion prohibits the MDSCs infiltration and blocks tumor development by increasing the number of cytotoxic T cells [61][43]. The role of neutrophils educated by cancer cells, or tumor-associated neutrophils (TAN), has received less attention in the PTME. Evidence showed that TANs contribute to pancreatic cancer cell spreading by producing multiple enzymes, namely matrix metalloproteinase (MMP) 8 and MMP9, Cathepsin-B, and proteinase-3, which accelerate the degradation of the ECM, break down the barrier, and promote cancer invasion and metastasis [62][44]. Neutrophil extracellular traps (NETs) are responsible for the exclusion of cytotoxic CD8+ T cells from tumors and may have a role in driving pancreatic cancer metastasis [63,64][45][46]. In preclinical models, lorlatinib, a TANs suppressor, attenuates pancreatic cancer growth and improves the efficacy of immune checkpoint inhibitors [65][47]. Similarly, the inhibition of neutrophil activator IL17 increased immune checkpoint blockade (PD-1, CTLA4) sensitivity [63][45]. The ECM in the pancreatic tumor microenvironment also appears to contribute to immunosuppression [66][48]: the thick, fibrotic ECM inhibits tumor vascularization and immune cell infiltration, as well as the delivery of drugs into tumors [67][49]. Thus, a suggested strategy is to bring back the normalization in the tumor immune ecosystem and make the immune backbone of the tumor hot or immunogenic so that it would be more responsive to therapy [53,68][35][50]. Although some studies have shown that an immunologic subtype of pancreatic cancer does exist and generally has a better prognosis than the unselected patient population [69,70][51][52], the treatment of immunosuppressive PDAC remains a major obstacle. The targeting of various contributors of the immune microenvironment in combination with immune checkpoint inhibitors is promising for synergistic antitumoral effects in preclinical models of pancreatic cancer and some ongoing clinical trials.

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021, 71, 209–249.
  2. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer Statistics, 2021. CA Cancer J. Clin. 2021, 71, 7–33.
  3. Najafi, M.; Majidpoor, J.; Toolee, H.; Mortezaee, K. The current knowledge concerning solid cancer and therapy. J. Biochem. Mol. Toxicol. 2021, 35, e22900.
  4. Neuzillet, C.; Tijeras-Raballand, A.; Ragulan, C.; Cros, J.; Patil, Y.; Martinet, M.; Erkan, M.; Kleeff, J.; Wilson, J.; Apte, M.; et al. Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma. J. Pathol. 2019, 248, 51–65.
  5. Bernard, V.; Semaan, A.; Huang, J.; San Lucas, F.A.; Mulu, F.C.; Stephens, B.M.; Guerrero, P.A.; Huang, Y.; Zhao, J.; Kamyabi, N.; et al. Single-Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression. Clin. Cancer Res. 2019, 25, 2194–2205.
  6. Singhi, A.D.; Wood, L.D. Early detection of pancreatic cancer using DNA-based molecular approaches. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 457–468.
  7. Mizrahi, J.D.; Surana, R.; Valle, J.W.; Shroff, R.T. Pancreatic cancer. Lancet 2020, 395, 2008–2020.
  8. van Dam, J.L.; Janssen, Q.P.; Besselink, M.G.; Homs, M.Y.V.; van Santvoort, H.C.; van Tienhoven, G.; de Wilde, R.F.; Wilmink, J.W.; van Eijck, C.H.J.; Groot Koerkamp, B. Dutch Pancreatic Cancer Group Neoadjuvant therapy or upfront surgery for resectable and borderline resectable pancreatic cancer: A meta-analysis of randomised controlled trials. Eur. J. Cancer 2022, 160, 140–149.
  9. Strobel, O.; Neoptolemos, J.; Jäger, D.; Büchler, M.W. Optimizing the outcomes of pancreatic cancer surgery. Nat. Rev. Clin. Oncol. 2019, 16, 11–26.
  10. Yu, S.; Zhang, C.; Xie, K.-P. Therapeutic resistance of pancreatic cancer: Roadmap to its reversal. Biochim. Biophys. Acta Rev. Cancer 2021, 1875, 188461.
  11. Thomasian, N.M.; Kamel, I.R.; Bai, H.X. Machine intelligence in non-invasive endocrine cancer diagnostics. Nat. Rev. Endocrinol. 2022, 18, 81–95.
  12. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674.
  13. Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 2017, 32, 185–203.e13.
  14. Makohon-Moore, A.; Iacobuzio-Donahue, C.A. Pancreatic cancer biology and genetics from an evolutionary perspective. Nat. Rev. Cancer 2016, 16, 553–565.
  15. Bailey, P.; Chang, D.K.; Nones, K.; Johns, A.L.; Patch, A.-M.; Gingras, M.-C.; Miller, D.K.; Christ, A.N.; Bruxner, T.J.C.; Quinn, M.C.; et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016, 531, 47–52.
  16. Humphris, J.L.; Patch, A.-M.; Nones, K.; Bailey, P.J.; Johns, A.L.; McKay, S.; Chang, D.K.; Miller, D.K.; Pajic, M.; Kassahn, K.S.; et al. Hypermutation in pancreatic cancer. Gastroenterology 2017, 152, 68–74.e2.
  17. Nevala-Plagemann, C.; Hidalgo, M.; Garrido-Laguna, I. From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer. Nat. Rev. Clin. Oncol. 2020, 17, 108–123.
  18. Warburg, O.; Wind, F.; Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 1927, 8, 519–530.
  19. Denko, N.C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer 2008, 8, 705–713.
  20. Encarnación-Rosado, J.; Kimmelman, A.C. Harnessing metabolic dependencies in pancreatic cancers. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 482–492.
  21. Dey, P.; Li, J.; Zhang, J.; Chaurasiya, S.; Strom, A.; Wang, H.; Liao, W.-T.; Cavallaro, F.; Denz, P.; Bernard, V.; et al. Oncogenic KRAS-Driven Metabolic Reprogramming in Pancreatic Cancer Cells Utilizes Cytokines from the Tumor Microenvironment. Cancer Discov. 2020, 10, 608–625.
  22. Zhao, J.-S.; Shi, S.; Qu, H.-Y.; Keckesova, Z.; Cao, Z.-J.; Yang, L.-X.; Yu, X.; Feng, L.; Shi, Z.; Krakowiak, J.; et al. Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth. Nat. Metab. 2022, 4, 239–253.
  23. Perera, R.M.; Stoykova, S.; Nicolay, B.N.; Ross, K.N.; Fitamant, J.; Boukhali, M.; Lengrand, J.; Deshpande, V.; Selig, M.K.; Ferrone, C.R.; et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 2015, 524, 361–365.
  24. 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.
  25. 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.
  26. Gupta, S.; Yano, J.; Mercier, V.; Htwe, H.H.; Shin, H.R.; Rademaker, G.; Cakir, Z.; Ituarte, T.; Wen, K.W.; Kim, G.E.; et al. Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth. Nat. Cell Biol. 2021, 23, 232–242.
  27. Halbrook, C.J.; Lyssiotis, C.A. Employing metabolism to improve the diagnosis and treatment of pancreatic cancer. Cancer Cell 2017, 31, 5–19.
  28. Ligorio, M.; Sil, S.; Malagon-Lopez, J.; Nieman, L.T.; Misale, S.; Di Pilato, M.; Ebright, R.Y.; Karabacak, M.N.; Kulkarni, A.S.; Liu, A.; et al. Stromal microenvironment shapes the intratumoral architecture of pancreatic cancer. Cell 2019, 178, 160–175.e27.
  29. Menezes, S.; Okail, M.H.; Jalil, S.M.A.; Kocher, H.M.; Cameron, A.J.M. Cancer-associated fibroblasts in pancreatic cancer: New subtypes, new markers, new targets. J. Pathol. 2022, 257, 526–544.
  30. 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.
  31. Gabitova-Cornell, L.; Surumbayeva, A.; Peri, S.; Franco-Barraza, J.; Restifo, D.; Weitz, N.; Ogier, C.; Goldman, A.R.; Hartman, T.R.; Francescone, R.; et al. Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer. Cancer Cell 2020, 38, 567–583.e11.
  32. Pereira, B.A.; Vennin, C.; Papanicolaou, M.; Chambers, C.R.; Herrmann, D.; Morton, J.P.; Cox, T.R.; Timpson, P. CAF subpopulations: A new reservoir of stromal targets in pancreatic cancer. Trends Cancer 2019, 5, 724–741.
  33. Öhlund, 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.
  34. Biffi, G.; Oni, T.E.; Spielman, B.; Hao, Y.; Elyada, E.; Park, Y.; Preall, J.; Tuveson, D.A. IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancer Discov. 2019, 9, 282–301.
  35. Mortezaee, K. Enriched cancer stem cells, dense stroma, and cold immunity: Interrelated events in pancreatic cancer. J. Biochem. Mol. Toxicol. 2021, 35, e22708.
  36. Evans, R.A.; Diamond, M.S.; Rech, A.J.; Chao, T.; Richardson, M.W.; Lin, J.H.; Bajor, D.L.; Byrne, K.T.; Stanger, B.Z.; Riley, J.L.; et al. Lack of immunoediting in murine pancreatic cancer reversed with neoantigen. JCI Insight 2016, 1, e88328.
  37. Binnewies, M.; Roberts, E.W.; Kersten, K.; Chan, V.; Fearon, D.F.; Merad, M.; Coussens, L.M.; Gabrilovich, D.I.; Ostrand-Rosenberg, S.; Hedrick, C.C.; et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 2018, 24, 541–550.
  38. Mazzieri, R.; Pucci, F.; Moi, D.; Zonari, E.; Ranghetti, A.; Berti, A.; Politi, L.S.; Gentner, B.; Brown, J.L.; Naldini, L.; et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 2011, 19, 512–526.
  39. Halbrook, C.J.; Pontious, C.; Kovalenko, I.; Lapienyte, L.; Dreyer, S.; Lee, H.-J.; Thurston, G.; Zhang, Y.; Lazarus, J.; Sajjakulnukit, P.; et al. Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer. Cell Metab. 2019, 29, 1390–1399.e6.
  40. Greten, T.F. Myeloid-derived suppressor cells in pancreatic cancer: More than a hidden barrier for antitumour immunity? Gut 2014, 63, 1690–1691.
  41. Das, S.; Shapiro, B.; Vucic, E.A.; Vogt, S.; Bar-Sagi, D. Tumor Cell-Derived IL1β Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer. Cancer Res. 2020, 80, 1088–1101.
  42. Zhang, Y.; Velez-Delgado, A.; Mathew, E.; Li, D.; Mendez, F.M.; Flannagan, K.; Rhim, A.D.; Simeone, D.M.; Beatty, G.L.; Pasca di Magliano, M. Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer. Gut 2017, 66, 124–136.
  43. Bayne, L.J.; Beatty, G.L.; Jhala, N.; Clark, C.E.; Rhim, A.D.; Stanger, B.Z.; Vonderheide, R.H. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 2012, 21, 822–835.
  44. Coffelt, S.B.; Wellenstein, M.D.; de Visser, K.E. Neutrophils in cancer: Neutral no more. Nat. Rev. Cancer 2016, 16, 431–446.
  45. Zhang, Y.; Chandra, V.; Riquelme Sanchez, E.; Dutta, P.; Quesada, P.R.; Rakoski, A.; Zoltan, M.; Arora, N.; Baydogan, S.; Horne, W.; et al. Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer. J. Exp. Med. 2020, 217, e20190354.
  46. Deng, J.; Kang, Y.; Cheng, C.-C.; Li, X.; Dai, B.; Katz, M.H.; Men, T.; Kim, M.P.; Koay, E.A.; Huang, H.; et al. DDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasis. JCI Insight 2021, 6, e146133.
  47. Nielsen, S.R.; Strøbech, J.E.; Horton, E.R.; Jackstadt, R.; Laitala, A.; Bravo, M.C.; Maltese, G.; Jensen, A.R.D.; Reuten, R.; Rafaeva, M.; et al. Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade. Nat. Commun. 2021, 12, 3414.
  48. 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.
  49. Shah, V.M.; Sheppard, B.C.; Sears, R.C.; Alani, A.W. Hypoxia: Friend or Foe for drug delivery in Pancreatic Cancer. Cancer Lett. 2020, 492, 63–70.
  50. Ullman, N.A.; Burchard, P.R.; Dunne, R.F.; Linehan, D.C. Immunologic strategies in pancreatic cancer: Making cold tumors hot. J. Clin. Oncol. 2022, 40, JCO2102616.
  51. Zhang, Z.; Ji, S.; Zhang, B.; Liu, J.; Qin, Y.; Xu, J.; Yu, X. Role of angiogenesis in pancreatic cancer biology and therapy. Biomed. Pharmacother. 2018, 108, 1135–1140.
  52. Danilova, L.; Ho, W.J.; Zhu, Q.; Vithayathil, T.; De Jesus-Acosta, A.; Azad, N.S.; Laheru, D.A.; Fertig, E.J.; Anders, R.; Jaffee, E.M.; et al. Programmed Cell Death Ligand-1 (PD-L1) and CD8 Expression Profiling Identify an Immunologic Subtype of Pancreatic Ductal Adenocarcinomas with Favorable Survival. Cancer Immunol. Res. 2019, 7, 886–895.
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