Skip to main content

Advertisement

SpringerLink
Log in

Cancer-Associated Fibroblasts Enhance Survival and Progression of the Aggressive Pancreatic Tumor Via FGF-2 and CXCL8

  • Original Article
  • Published:
Cancer Microenvironment

Abstract

Pancreatic ductal adenocarcinoma remains one of the most challenging human cancers. Desmoplasia is predominant in this disease exhibiting a strong stromal reaction with an abundance of the cancer-associated fibroblasts (CAFs). We aimed in this study to investigate the reciprocal interaction between the tumor cells and the CAFs and its effect on tumor cells survival. We hypothesized that the survival of pancreatic cancer cell with aggressive phenotype is modulated by the Interactions between malignant pancreatic tumor cells and surrounding CAFs. To examine this, we utilized co-culture methods where tumor cells with different malignant potentials, HPAF (low) HPAF-CD11 (moderate/high) co-cultured with CAFs. CAFs-conditioned media increased the growth of HPAF-CD11 but not HPAF cells and increased CXCL8 levels highly in HPAF-CD11 and slightly in HPAF. The growth stimulatory effect and elevated CXCL8 level caused by CAFs-conditioned media were diminished by neutralizing the fibroblast growth factor-2 (FGF-2). In addition, conditioned media of HPAF-CD11 increased CAFs cell number whereas that of HPAF did not, and these effects were suppressed by neutralizing CXCL8. Furthermore, data from gene expression microarray study exhibited different expression profiles between HPAF and HPAF-CD11 when co-culture with CAFs. A significant increase in CXCL8 and FGF-2 expression was observed with HPAF-CD11/CAFs co-culture and to a lower extent with HPAF/CAFs co-culture. Together, these data demonstrate a paracrine bi-directional interaction between pancreatic tumor cells and the CAFs through CXCL8 and FGF-2 that helps the tumor growth. Future in-depth study of these pathways will assist in obtaining diagnostic and therapeutic tools for pancreatic ductal adenocarcinoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68(1):7–30. https://doi.org/10.3322/caac.21442

    Article  PubMed  Google Scholar 

  2. Warshaw AL, Fernandez-del Castillo C (1992) Pancreatic carcinoma. N Engl J Med 326(7):455–465. https://doi.org/10.1056/NEJM199202133260706

    Article  CAS  PubMed  Google Scholar 

  3. Kuniyasu H, Abbruzzese JL, Cleary KR, Fidler IJ (2001) Induction of ductal and stromal hyperplasia by basic fibroblast growth factor produced by human pancreatic carcinoma. Int J Oncol 19(4):681–685

    CAS  PubMed  Google Scholar 

  4. Iacobuzio-Donahue CA, Ryu B, Hruban RH, Kern SE (2002) Exploring the host desmoplastic response to pancreatic carcinoma: gene expression of stromal and neoplastic cells at the site of primary invasion. Am J Pathol 160(1):91–99. https://doi.org/10.1016/S0002-9440(10)64353-2

    Article  PubMed  PubMed Central  Google Scholar 

  5. Watanabe I, Hasebe T, Sasaki S, Konishi M, Inoue K, Nakagohri T et al (2003) Advanced pancreatic ductal cancer: fibrotic focus and beta-catenin expression correlate with outcome. Pancreas 26(4):326–333

    Article  CAS  PubMed  Google Scholar 

  6. Seymour AB, Hruban RH, Redston M, Caldas C, Powell SM, Kinzler KW et al (1994) Allelotype of pancreatic adenocarcinoma. Cancer Res 54(10):2761–2764

    CAS  PubMed  Google Scholar 

  7. Kalluri R (2016) The biology and function of fibroblasts in cancer. Nat Rev Cancer 16(9):582–598. https://doi.org/10.1038/nrc.2016.73

    Article  CAS  PubMed  Google Scholar 

  8. Kloppel G, Lingenthal G, von Bulow M, Kern HF (1985) Histological and fine structural features of pancreatic ductal adenocarcinomas in relation to growth and prognosis: studies in xenografted tumours and clinico-histopathological correlation in a series of 75 cases. Histopathology 9(8):841–856

    Article  CAS  PubMed  Google Scholar 

  9. Ryu B, Jones J, Hollingsworth MA, Hruban RH, Kern SE (2001) Invasion-specific genes in malignancy: serial analysis of gene expression comparisons of primary and passaged cancers. Cancer Res 61(5):1833–1838

    CAS  PubMed  Google Scholar 

  10. Öhlund D, Elyada E, Tuveson D (2014) Fibroblast heterogeneity in the cancer wound. J Exp Med 211(8):1503–1523. https://doi.org/10.1084/jem.20140692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Moir JA, Mann J, White SA (2015) The role of pancreatic stellate cells in pancreatic cancer. Surg Oncol 24(3):232–238. https://doi.org/10.1016/j.suronc.2015.05.002

    Article  PubMed  Google Scholar 

  12. Omary MB, Lugea A, Lowe AW, Pandol SJ (2007) The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest 117(1):50–59. https://doi.org/10.1172/jci30082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Apte MV, Wilson JS, Lugea A, Pandol SJ (2013) A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 144(6):1210–1219. https://doi.org/10.1053/j.gastro.2012.11.037

    Article  PubMed  Google Scholar 

  14. Apte M, Pirola RC, Wilson JS (2015) Pancreatic stellate cell: physiologic role, role in fibrosis and cancer. Curr Opin Gastroenterol 31(5):416–423. https://doi.org/10.1097/mog.0000000000000196

    Article  CAS  PubMed  Google Scholar 

  15. Xu Z, Vonlaufen A, Phillips PA, Fiala-Beer E, Zhang X, Yang L et al (2010) Role of pancreatic stellate cells in pancreatic Cancer metastasis. Am J Pathol 177(5):2585–2596. https://doi.org/10.2353/ajpath.2010.090899

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lonardo E, Frias-Aldeguer J, Hermann PC, Heeschen C (2012) Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness. Cell Cycle 11(7):1282–1290. https://doi.org/10.4161/cc.19679

    Article  CAS  PubMed  Google Scholar 

  17. McCarroll JA, Naim S, Sharbeen G, Russia N, Lee J, Kavallaris M et al (2014) Role of pancreatic stellate cells in chemoresistance in pancreatic cancer. Front Physiol 5:141. https://doi.org/10.3389/fphys.2014.00141

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zambirinis CP, Levie E, Nguy S, Avanzi A, Barilla R, Xu Y et al (2015) TLR9 ligation in pancreatic stellate cells promotes tumorigenesis. J Exp Med 212(12):2077–2094. https://doi.org/10.1084/jem.20142162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Grey AM, Schor AM, Rushton G, Ellis I, Schor SL (1989) Purification of the migration stimulating factor produced by fetal and breast cancer patient fibroblasts. Proc Natl Acad Sci U S A 86(7):2438–2442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Camps JL, Chang SM, Hsu TC, Freeman MR, Hong SJ, Zhau HE et al (1990) Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc Natl Acad Sci U S A 87(1):75–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hart IR (1982) 'Seed and soil' revisited: mechanisms of site-specific metastasis. Cancer Metastasis Rev 1(1):5–16

    Article  CAS  PubMed  Google Scholar 

  22. Paget S (1989) The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 8(2):98–101

    CAS  PubMed  Google Scholar 

  23. Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2(8):563–572. https://doi.org/10.1038/nrc865

    Article  CAS  PubMed  Google Scholar 

  24. Fidler IJ, Yano S, Zhang RD, Fujimaki T, Bucana CD (2002) The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 3(1):53–57

    Article  CAS  PubMed  Google Scholar 

  25. Maehara N, Matsumoto K, Kuba K, Mizumoto K, Tanaka M, Nakamura T (2001) NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells. Br J Cancer 84(6):864–873. https://doi.org/10.1054/bjoc.2000.1682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Qian LW, Mizumoto K, Maehara N, Ohuchida K, Inadome N, Saimura M et al (2003) Co-cultivation of pancreatic cancer cells with orthotopic tumor-derived fibroblasts: fibroblasts stimulate tumor cell invasion via HGF secretion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production. Cancer Lett 190(1):105–112

    Article  CAS  PubMed  Google Scholar 

  27. Apte MV, Wilson JS (2004) Mechanisms of pancreatic fibrosis. Dig Dis 22(3):273–279. https://doi.org/10.1159/000082799

    Article  CAS  PubMed  Google Scholar 

  28. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D et al (2009) Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic Cancer. Science 324(5933):1457–1461. https://doi.org/10.1126/science.1171362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Provenzano PP, Cuevas C, Chang AE, Goel VK, Hoff V, Daniel D, Hingorani SR (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21(3):418–429. https://doi.org/10.1016/j.ccr.2012.01.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK et al (2012) Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62(1):112–120. https://doi.org/10.1136/gutjnl-2012-302529

    Article  CAS  PubMed  Google Scholar 

  31. Micke P, tman A (2004) Tumour-stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy? Lung Cancer 45:S163–S175. https://doi.org/10.1016/j.lungcan.2004.07.977

    Article  PubMed  Google Scholar 

  32. Paulsson J, Micke P (2014) Prognostic relevance of cancer-associated fibroblasts in human cancer. Semin Cancer Biol 25:61–68. https://doi.org/10.1016/j.semcancer.2014.02.006

    Article  CAS  PubMed  Google Scholar 

  33. De Wever O, Mareel M (2003) Role of tissue stroma in cancer cell invasion. J Pathol 200(4):429–447. https://doi.org/10.1002/path.1398

    Article  CAS  PubMed  Google Scholar 

  34. Cheng N, Bhowmick NA, Chytil A, Gorksa AE, Brown KA, Muraoka R et al (2005) Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks. Oncogene 24(32):5053–5068. https://doi.org/10.1038/sj.onc.1208685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Basilico C, Moscatelli D (1992) The FGF family of growth factors and oncogenes. Adv Cancer Res 59:115–165

    Article  CAS  PubMed  Google Scholar 

  36. Polnaszek N, Kwabi-Addo B, Peterson LE, Ozen M, Greenberg NM, Ortega S et al (2003) Fibroblast growth factor 2 promotes tumor progression in an autochthonous mouse model of prostate cancer. Cancer Res 63(18):5754–5760

    CAS  PubMed  Google Scholar 

  37. Kleeff J, Kothari NH, Friess H, Fan H, Korc M (2004) Adenovirus-mediated transfer of a truncated fibroblast growth factor (FGF) type I receptor blocks FGF-2 signaling in multiple pancreatic cancer cell lines. Pancreas 28(1):25–30

    Article  CAS  PubMed  Google Scholar 

  38. Coleman SJ, Chioni A-M, Ghallab M, Anderson RK, Lemoine NR, Kocher HM et al (2014) Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion. EMBO Mol Med 6(4):467–481. https://doi.org/10.1002/emmm.201302698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Purohit A, Varney M, Rachagani S, Ouellette MM, Batra SK, Singh RK (2016) CXCR2 signaling regulates KRAS(G(1)(2)D)-induced autocrine growth of pancreatic cancer. Oncotarget 7(6):7280–7296. https://doi.org/10.18632/oncotarget.6906

    Article  PubMed  PubMed Central  Google Scholar 

  40. Liu Q, Li A, Tian Y, Wu JD, Liu Y, Li T et al (2016) The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev 31:61–71. https://doi.org/10.1016/j.cytogfr.2016.08.002

    Article  PubMed  PubMed Central  Google Scholar 

  41. Saintigny P, Massarelli E, Lin S, Ahn YH, Chen Y, Goswami S et al (2012) CXCR2 expression in tumor cells is a poor prognostic factor and promotes invasion and metastasis in lung adenocarcinoma. Cancer Res 73(2):571–582. https://doi.org/10.1158/0008-5472.can-12-0263

    Article  PubMed  PubMed Central  Google Scholar 

  42. Giri D, Ittmann M (2001) Interleukin-8 is a paracrine inducer of fibroblast growth factor 2, a stromal and epithelial growth factor in benign prostatic hyperplasia. Am J Pathol 159(1):139–147. https://doi.org/10.1016/S0002-9440(10)61681-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim YW, Kern HF, Mullins TD, Koriwchak MJ, Metzgar RS (1989) Characterization of clones of a human pancreatic adenocarcinoma cell line representing different stages of differentiation. Pancreas 4(3):353–362

    Article  CAS  PubMed  Google Scholar 

  44. Egami H, Takiyama Y, Chaney WG, Cano M, Fujii H, Tomioka T et al (1990) Comparative studies on expression of tumor-associated antigens in human and induced pancreatic cancer in Syrian hamsters. Int J Pancreatol 7(1–3):91–100

    CAS  PubMed  Google Scholar 

  45. Batra SK, Metzgar RS, Hollingsworth MA (1991) Isolation and characterization of a complementary DNA (PD-1) differentially expressed by human pancreatic ductal cell tumors. Cell Growth Differ 2(8):385–390

    CAS  PubMed  Google Scholar 

  46. Wang QJ, Knezetic JA, Schally AV, Pour PM, Adrian TE (1996) Bombesin may stimulate proliferation of human pancreatic cancer cells through an autocrine pathway. Int J Cancer 68(4):528–534. https://doi.org/10.1002/(SICI)1097-0215(19961115)68:4<528::AID-IJC20>3.0.CO;2-#

  47. Ding XZ, Fehsenfeld DM, Murphy LO, Permert J, Adrian TE (2000) Physiological concentrations of insulin augment pancreatic cancer cell proliferation and glucose utilization by activating MAP kinase, PI3 kinase and enhancing GLUT-1 expression. Pancreas 21(3):310–320

    Article  CAS  PubMed  Google Scholar 

  48. Saxena S, Purohit A, Varney ML, Hayashi Y, Singh RK (2018) Semaphorin-5A maintains epithelial phenotype of malignant pancreatic cancer cells. BMC Cancer 18(1):1283. https://doi.org/10.1186/s12885-018-5204-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mizuguchi H, Utoguchi N, Mayumi T (1997) Preparation of glial extracellular matrix: a novel method to analyze glial-endothelial cell interaction. Brain Res Protocol 1(4):339–343

    Article  CAS  Google Scholar 

  50. Le X, Shi Q, Wang B, Xiong Q, Qian C, Peng Z et al (2000) Molecular regulation of constitutive expression of interleukin-8 in human pancreatic adenocarcinoma. J Interf Cytokine Res 20(11):935–946. https://doi.org/10.1089/10799900050198372

    Article  CAS  Google Scholar 

  51. Takamori H, Oades ZG, Hoch RC, Burger M, Schraufstatter IU (2000) Autocrine growth effect of IL-8 and GRO?? On a human pancreatic Cancer cell line, Capan-1. Pancreas 21(1):52–56. https://doi.org/10.1097/00006676-200007000-00051

    Article  CAS  PubMed  Google Scholar 

  52. Frick VO, Rubie C, Wagner M, Graeber S, Grimm H, Kopp B et al (2008) Enhanced ENA-78 and IL-8 expression in patients with malignant pancreatic diseases. Pancreatology 8(4–5):488–497. https://doi.org/10.1159/000151776

    Article  CAS  PubMed  Google Scholar 

  53. Strieter RM, Burdick MD, Mestas J, Gomperts B, Keane MP, Belperio JA (2006) Cancer CXC chemokine networks and tumour angiogenesis. Eur J Cancer 42(6):768–778. https://doi.org/10.1016/j.ejca.2006.01.006

    Article  CAS  PubMed  Google Scholar 

  54. Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, Morse E et al (2014) Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med 6(237):237ra267–237ra267. https://doi.org/10.1126/scitranslmed.3007974

    Article  CAS  Google Scholar 

  55. Chan TS, Hsu CC, Pai VC, Liao WY, Huang SS, Tan KT et al (2016) Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells. J Exp Med 213(13):2967–2988. https://doi.org/10.1084/jem.20151665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tuxhorn JA, Ayala GE, Smith MJ, Smith VC, Dang TD, Rowley DR (2002) Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling. Clin Cancer Res 8(9):2912–2923

    CAS  PubMed  Google Scholar 

  57. Ohuchida K, Mizumoto K, Murakami M, Qian LW, Sato N, Nagai E et al (2004) Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res 64(9):3215–3222

    Article  CAS  PubMed  Google Scholar 

  58. Muerkoster S, Wegehenkel K, Arlt A, Witt M, Sipos B, Kruse ML et al (2004) Tumor stroma interactions induce chemoresistance in pancreatic ductal carcinoma cells involving increased secretion and paracrine effects of nitric oxide and interleukin-1beta. Cancer Res 64(4):1331–1337

    Article  PubMed  Google Scholar 

  59. Yamanaka Y, Friess H, Buchler M, Beger HG, Uchida E, Onda M et al (1993) Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res 53(21):5289–5296

    CAS  PubMed  Google Scholar 

  60. Relf M, LeJeune S, Scott PA, Fox S, Smith K, Leek R et al (1997) Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 57(5):963–969

    CAS  PubMed  Google Scholar 

  61. Feng S, Wang F, Matsubara A, Kan M, McKeehan WL (1997) Fibroblast growth factor receptor 2 limits and receptor 1 accelerates tumorigenicity of prostate epithelial cells. Cancer Res 57(23):5369–5378

    CAS  PubMed  Google Scholar 

  62. Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F et al (1996) Receptor specificity of the fibroblast growth factor family. J Biol Chem 271(25):15292–15297

    Article  CAS  PubMed  Google Scholar 

  63. Li A, Dubey S, Varney ML, Dave BJ, Singh RK (2003) IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 170(6):3369–3376

    Article  CAS  PubMed  Google Scholar 

  64. Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14(21):6735–6741. https://doi.org/10.1158/1078-0432.CCR-07-4843

    Article  CAS  PubMed  Google Scholar 

  65. Sanui T (2003) DOCK2 regulates Rac activation and cytoskeletal reorganization through interaction with ELMO1. Blood 102(8):2948–2950. https://doi.org/10.1182/blood-2003-01-0173

    Article  CAS  PubMed  Google Scholar 

  66. Grimsley CM, Kinchen JM, Tosello-Trampont A-C, Brugnera E, Haney LB, Lu M et al (2003) Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration. J Biol Chem 279(7):6087–6097. https://doi.org/10.1074/jbc.m307087200

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. M. Hollingsworth and Dr. S.K. Batra from University of Nebraska Medical Center, Omaha, NE for providing the pancreatic cancer cell lines, and the pancreatic CAFs cell line. This work was supported in part by grants U54CA163120, R01CA228524, and Cancer Center Support Grant (P30CA036727) from the National Cancer Institute, National Institutes of Health. Mohammad Awaji as a graduate student was supported by a scholarship from King Fahad Specialist Hospital-Dammam and the Saudi Arabian Cultural mission in the USA, and a pre-doctoral fellowship from the University of Nebraska Medical Center.

Author information

Authors and Affiliations

  1. Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Ctr., Omaha, NE, 68198-5900, United States

    Mohammad Awaji, Mitsuru Futakuchi, Tayla Heavican, Javeed Iqbal & Rakesh K. Singh

  2. Department of Pathology and Laboratory Medicine, King Fahad Specialist Hospital-Dammam, Dammam, 31444, Saudi Arabia

    Mohammad Awaji

  3. Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Mitsuru Futakuchi

Authors
  1. Mohammad Awaji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mitsuru Futakuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tayla Heavican
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Javeed Iqbal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rakesh K. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rakesh K. Singh.

Ethics declarations

Conflict of Interest

The authors declare no potential conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Awaji, M., Futakuchi, M., Heavican, T. et al. Cancer-Associated Fibroblasts Enhance Survival and Progression of the Aggressive Pancreatic Tumor Via FGF-2 and CXCL8. Cancer Microenvironment 12, 37–46 (2019). https://doi.org/10.1007/s12307-019-00223-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12307-019-00223-3

Keywords

Search

Navigation