CoChat
Sign Up
Cited by 34Pancreatic and Hepatic Oncology ResearchCancer Cells and MetastasisCellular Mechanics and Interactions

Subcutaneous Inoculation of 3D Pancreatic Cancer Spheroids Results in Development of Reproducible Stroma-Rich Tumors

Open access
Durymanov, Mikhail, Kroll, Christian, Permyakova, Anastasia, O'Neill, Elizabeth, Sulaiman, Raed, Person, Michael, Reineke, Joshua·2019·Translational Oncology
DOI 10.1016/j.tranon.2018.10.003PMC PMC6295361
Open this paper in CoChat — free accountOpen PDF

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by high expression of extracellular matrix in tumor tissue, which contributes to chemoresistance and poor prognosis. Here, we developed 3D pancreatic cancer spheroids, based on pancreatic cancer cells and fibroblast co-culture, which demonstrate innate desmoplastic properties and stay poorly permeable for model nanoparticles. Our study revealed that establishment of tumors by transplantation of spheroids significantly improved subcutaneous xenograft model of PDAC, which stays the most widely used animal model for testing of new drugs and drug delivery approaches. Spheroid based tumors abundantly produced different extracellular matrix (ECM) components including collagen I, fibronectin, laminin and hyaluronic acid. These tumors were highly reproducible with excellent uniformity in terms of ECM architecture recapitulating clinical PDAC tumors, whereas in more common cell based xenografts a significant intertumor heterogeneity in extracellular matrix production was found. Moreover, spheroid based xenografts demonstrated higher expression of pro-fibrotic and pro-survival PDAC hallmarks in opposite to cell based counterparts. We believe that future development of this model will provide an effective instrument for testing of anti-cancer drugs with improved predictive value.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.tranon.2018.10.003

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Tumor spheroids display enhanced deposition of tumor ECM proteins (e.g., fibronectin, lumican, laminin, and collagen type I and VI) compared to 2D cell culture models.

    “Several studies have shown that tumor spheroids display an enhanced deposition of tumor ECM proteins (e.g., fibronectin, lumican, laminin, and collagen type I and VI) [118,121,122,123] in comparison to 2D cell culture models.”

    From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [121]

    The Results section on ECM production in 3D pancreatic spheroids reports deposition of fibronectin and fibrillar collagen I in PANC-1/3T3 spheroids, and detects laminin. It does not report lumican or collagen VI, and its spheroid comparisons are with other spheroids, not 2D cell cultures. The separate Results comparison concerns spheroid-derived versus cell-injection xenografts, so it does not establish the stated 3D-versus-2D culture comparison. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 48 · Cited by 34

Research works printed but not linked: 43

  1. [1]Whatcott CJ Posner RG Von Hoff DD Han H Desmoplasia and chemoresistance in pancreatic cancer Grippo PJ Munshi HG Pancreat. Cancer Tumor Microenviron 2012 Transworld Research Network Trivandrum (India) http://www.ncbi.nlm.nih.gov/books/NBK98939/ 22876390
  2. [2]Tamburrino A Piro G Carbone C Tortora G Melisi D Mechanisms of resistance to chemotherapeutic and anti-angiogenic drugs as novel targets for pancreatic cancer therapy Front Pharmacol 4 2013 56 23641216 PMC3639407
  3. [3]Omary MB Lugea A Lowe AW Pandol SJ The pancreatic stellate cell: a star on the rise in pancreatic diseases J Clin Invest 117 2007 50 59 17200706 PMC1716214
  4. [4]Zhan H-X Zhou B Cheng Y-G Xu J-W Wang L Zhang G-Y Hu S-Y Crosstalk between stromal cells and cancer cells in pancreatic cancer: New insights into stromal biology Cancer Lett 392 2017 83 93 28189533
  5. [5]Vonlaufen A Phillips PA Xu Z Goldstein D Pirola RC Wilson JS Apte MV Pancreatic Stellate Cells and Pancreatic Cancer Cells: An Unholy Alliance Cancer Res 68 2008 7707 7710 18829522
  6. [6]Cirri P Chiarugi P Cancer associated fibroblasts: the dark side of the coin Am J Cancer Res 1 2011 482 497 21984967 PMC3186047
  7. [7]Rath N Olson MF Regulation of pancreatic cancer aggressiveness by stromal stiffening Nat Med 22 2016 462 463 27149218
  8. [8]Shields MA Dangi-Garimella S Redig AJ Munshi HG Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression Biochem J 441 2012 541 552 22187935 PMC8215985
  9. [9]Duan W Ma J Ma Q Xu Q Lei J Han L Li X Wang Z Wu Z Lv S The Activation of β1-integrin by Type I Collagen Coupling with the Hedgehog Pathway Promotes the Epithelial-Mesenchymal Transition in Pancreatic Cancer Curr Cancer Drug Targets 14 2014 446 457 24720337
  10. [10]Shintani Y Hollingsworth MA Wheelock MJ Johnson KR Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH(2)-terminal kinase 1 and up-regulating N-cadherin expression Cancer Res 66 2006 11745 11753 17178870
  11. [11]Huanwen W Zhiyong L Xiaohua S Xinyu R Kai W Tonghua L Intrinsic chemoresistance to gemcitabine is associated with constitutive and laminin-induced phosphorylation of FAK in pancreatic cancer cell lines Mol Cancer 8 2009 125 20021699 PMC2806309
  12. [12]Topalovski M Brekken RA Matrix control of pancreatic cancer: new insights into fibronectin signaling Cancer Lett 381 2016 252 258 26742464 PMC4927402
  13. [13]Sato N Kohi S Hirata K Goggins M Role of hyaluronan in pancreatic cancer biology and therapy: Once again in the spotlight Cancer Sci 107 2016 569 575 26918382 PMC4970823
  14. [14]Provenzano PP Hingorani SR Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer Br J Cancer 108 2013 1 8 23299539 PMC3553539
  15. [16]Ware MJ Keshishian V Law JJ Ho JC Favela CA Rees P Smith B Mohammad S Hwang RF Rajapakshe K Generation of an in vitro 3D PDAC stroma rich spheroid model Biomaterials 108 2016 129 142 27627810 PMC5082237
  16. [17]Priwitaningrum DL Blondé J-BG Sridhar A van Baarlen J Hennink WE Storm G Le Gac S Prakash J Tumor stroma-containing 3D spheroid arrays: A tool to study nanoparticle penetration J Control Release 244 2016 257 268 27616660
  17. [19]Carmeliet P Jain RK Angiogenesis in cancer and other diseases Nature 407 2000 249 257 11001068
  18. [20]Mantoni TS Lunardi S Al-Assar O Masamune A Brunner TB Pancreatic stellate cells radioprotect pancreatic cancer cells through β1-integrin signaling Cancer Res 71 2011 3453 3458 21558392 PMC3097171
  19. [21]Attieh Y Clark AG Grass C Richon S Pocard M Mariani P Elkhatib N Betz T Gurchenkov B Vignjevic DM Cancer-associated fibroblasts lead tumor invasion through integrin-β3-dependent fibronectin assembly J Cell Biol 216 2017 3509 3520 28931556 PMC5674886
  20. [22]Lee J Yakubov B Ivan C Jones DR Caperell-Grant A Fishel M Cardenas H Matei D Tissue Transglutaminase Activates Cancer-Associated Fibroblasts and Contributes to Gemcitabine Resistance in Pancreatic Cancer Neoplasia 18 2016 689 698 27792935 PMC5094382
  21. [23]Kadler KE Hill A Canty-Laird EG Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators Curr Opin Cell Biol 20 2008 495 501 18640274 PMC2577133
  22. [24]Kleeff J Kothari NH Friess H Fan H Korc M 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 2004 25 30 14707726
  23. [26]Herreros-Villanueva M Hijona E Cosme A Bujanda L Mouse models of pancreatic cancer World J Gastroenterol 18 2012 1286 1294 22493542 PMC3319955
  24. [27]Hwang C-I Boj SF Clevers H Tuveson DA Preclinical models of pancreatic ductal adenocarcinoma J Pathol 238 2016 197 204 26419819 PMC4700534
  25. [28]Erkan M Reiser-Erkan C Michalski CW Deucker S Sauliunaite D Streit S Esposito I Friess H Kleeff J Cancer-Stellate Cell Interactions Perpetuate the Hypoxia-Fibrosis Cycle in Pancreatic Ductal Adenocarcinoma Neoplasia 11 2009 497 508 19412434 PMC2671860
  26. [29]Lohse I Lourenco C Ibrahimov E Pintilie M Tsao M-S Hedley DW Assessment of Hypoxia in the Stroma of Patient-Derived Pancreatic Tumor Xenografts Cancer 6 2014 459 471 PMC3980617 24577243
  27. [30]Laird AK Dynamics of Tumour Growth Br J Cancer 18 1964 490 502 PMC2071101 14219541
  28. [31]Hwang RF Moore T Arumugam T Ramachandran V Amos KD Rivera A Ji B Evans DB Logsdon CD Cancer-Associated Stromal Fibroblasts Promote Pancreatic Tumor Progression Cancer Res 68 2008 918 926 18245495 PMC2519173
  29. [32]Liu Y Du L Role of pancreatic stellate cells and periostin in pancreatic cancer progression Tumour Biol 36 2015 3171 3177 25840689
  30. [33]Hirakawa T Yashiro M Doi Y Kinoshita H Morisaki T Fukuoka T Hasegawa T Kimura K Amano R Hirakawa K Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia PLoS One 11 2016 e0159912 PMC4972430 27487118
  31. [34]Wu Q Tian Y Zhang J Zhang H Gu F Lu Y Zou S Chen Y Sun P Xu M Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma Oncotarget 8 2017 102721 102738 29254283 PMC5731993
  32. [35]Hinz B Celetta G Tomasek JJ Gabbiani G Chaponnier C Alpha-smooth muscle actin expression upregulates fibroblast contractile activity Mol Biol Cell 12 2001 2730 2741 11553712 PMC59708
  33. [36]Velling T Risteli J Wennerberg K Mosher DF Johansson S Polymerization of Type I and III Collagens Is Dependent On Fibronectin and Enhanced By Integrins α11β1and α2β1 J Biol Chem 277 2002 37377 37381 12145303
  34. [37]Falasca M Selvaggi F Buus R Sulpizio S E. Edling C Targeting phosphoinositide 3-kinase pathways in pancreatic cancer--from molecular signalling to clinical trials Anticancer Agents Med Chem 11 2011 455 463 21521159
  35. [38]Yamamoto S Tomita Y Hoshida Y Morooka T Nagano H Dono K Umeshita K Sakon M Ishikawa O Ohigashi H Prognostic Significance of Activated Akt Expression in Pancreatic Ductal Adenocarcinoma Clin Cancer Res 10 2004 2846 2850 15102693
  36. [39]Neesse A Algül H Tuveson DA Gress TM Stromal biology and therapy in pancreatic cancer: a changing paradigm Gut 64 2015 1476 1484 25994217
  37. [40]Gore J Korc M Pancreatic cancer stroma: friend or foe? Cancer Cell 25 2014 711 712 24937454 PMC4821630
  38. [41]Durymanov MO Rosenkranz AA Sobolev AS Current Approaches for Improving Intratumoral Accumulation and Distribution of Nanomedicines Theranostics 5 2015 1007 1020 26155316 PMC4493538
  39. [42]Krempley BD Yu KH Preclinical models of pancreatic ductal adenocarcinoma Chin Clin Oncol 6 2017 25 28705002
  40. [43]Cassidy JW Caldas C Bruna A Maintaining Tumor Heterogeneity in Patient-Derived Tumor Xenografts Cancer Res 75 2015 2963 2968 26180079 PMC4539570
  41. [44]Sakai S Iwata C Tanaka HY Cabral H Morishita Y Miyazono K Kano MR Increased fibrosis and impaired intratumoral accumulation of macromolecules in a murine model of pancreatic cancer co-administered with FGF-2 J Control Release 230 2016 109 115 27080571
  42. [45]Huang L Holtzinger A Jagan I BeGora M Lohse I Ngai N Nostro C Wang R Muthuswamy LB Crawford HC Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids Nat Med 21 2015 1364 1371 26501191 PMC4753163
  43. [46]Boj SF Hwang C-I Baker LA Chio IIC Engle DD Corbo V Jager M Ponz-Sarvise M Tiriac H Spector MS Organoid models of human and mouse ductal pancreatic cancer Cell 160 2015 324 338 25557080 PMC4334572

Authors
Durymanov, M., Kroll, C., Permyakova, A., O'Neill, E., Sulaiman, R., Person, M., & Reineke, J.
Affiliations
  • South Dakota State University (US)
  • Avera Health (US)
  • Avera McKennan Hospital & University Health Center (US)
Corresponding author
Reineke, Joshua
ORCID
Venue
Translational Oncology
Publisher
Elsevier BV
Published
2019-01
Volume
12
Issue
1
Pages
180-189
ISSN
1936-5233 (ISSN-L)
DOI
10.1016/j.tranon.2018.10.003
PMC
PMC6295361
OpenAlex
W2898086946
Cited by
34
References
48
Citations by year
2026: 2 · 2025: 5 · 2024: 4 · 2023: 2 · 2022: 5 · 2021: 6 · 2020: 7 · 2019: 3
FWCI
1.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Oncology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • American Cancer Society Pilot Award (11-053-01-IRG)
  • South Dakota Board of Regents Competitive Research Grant Program
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
pancreatic ductal adenocarcinoma, subcutaneous xenograft, tumor stroma, extracellular matrix, desmoplasia, fibroblast co-culture, type I collagen, fibronectin, laminin, hyaluronic acid, intertumoral heterogeneity, drug delivery, nanoparticle permeability

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review