Advertisement

Clinical & Experimental Metastasis

, Volume 36, Issue 2, pp 97–108 | Cite as

The role of heterogeneous environment and docetaxel gradient in the emergence of polyploid, mesenchymal and resistant prostate cancer cells

  • Ke-Chih LinEmail author
  • Gonzalo Torga
  • Yusha Sun
  • Robert Axelrod
  • Kenneth J. Pienta
  • James C. Sturm
  • Robert H. Austin
Research Paper

Abstract

The ability of a population of PC3 prostate epithelial cancer cells to become resistant to docetaxel therapy and progress to a mesenchymal state remains a fundamental problem. The progression towards resistance is difficult to directly study in heterogeneous ecological environments such as tumors. In this work, we use a micro-fabricated “evolution accelerator” environment to create a complex heterogeneous yet controllable in-vitro environment with a spatially-varying drug concentration. With such a structure we observe the rapid emergence of a surprisingly large number of polyploid giant cancer cells (PGCCs) in regions of very high drug concentration, which does not occur in conventional cell culture of uniform concentration. This emergence of PGCCs in a high drug environment is due to migration of diploid epithelial cells from regions of low drug concentration, where they proliferate, to regions of high drug concentration, where they rapidly convert to PGCCs. Such a mechanism can only occur in spatially-varying rather than homogeneous environments. Further, PGCCs exhibit increased expression of the mesenchymal marker ZEB1 in the same high-drug regions where they are formed, suggesting the possible induction of an epithelial to mesenchymal transition (EMT) in these cells. This is consistent with prior work suggesting the PGCC cells are mediators of resistance in response to chemotherapeutic stress. Taken together, this work shows the key role of spatial heterogeneity and the migration of proliferative diploid cells to form PGCCs as a survival strategy for the cancer population, with implications for new therapies.

Keywords

Polyploid giant cancer cells Cancer-on-a-chip Tumor microenvironment Chemotherapy gradient Cell migration Metastasis 

Abbreviations

PGCC

Polyploid giant cancer cell

EA

Evolution accelerator

IF

Immunofluorescence

ZEB1

Zinc finger E-box-binding homeobox 1

Notes

Acknowledgements

We would like to thank fruitful discussions with Dr. Yibin Kang. This work was supported by NSF PHY-1659940.

Compliance with ethical standards

Conflict of interests

The authors declare no potential conflict of interests.

Supplementary material

10585_2019_9958_MOESM1_ESM.avi (25.8 mb)
Supplementary material Video (AVI 26417 KB)
10585_2019_9958_MOESM2_ESM.pdf (1.4 mb)
Supplementary material Figure 1 (PDF 1492 KB)
10585_2019_9958_MOESM3_ESM.pdf (282 kb)
Supplementary material Figure 2 (PDF 283 KB)
10585_2019_9958_MOESM4_ESM.pdf (10.1 mb)
Supplementary material Figure 3 (PDF 10337 KB)
10585_2019_9958_MOESM5_ESM.pdf (41 kb)
Supplementary material Table 1 (PDF 42 KB)

References

  1. 1.
    Wolberg WH, Nick Street W, Mangasarian OL (1999) Importance of nuclear morphology in breast cancer prognosis. Clin Cancer Res 5(11):3542–3548Google Scholar
  2. 2.
    Mittal K, Donthamsetty S, Kaur R, Yang C, Gupta MV, Reid MD, Choi DH, Rida PCG, Aneja R (2017) Multinucleated polyploidy drives resistance to Docetaxel chemotherapy in prostate cancer. Br J Cancer 116(9):1186–1194CrossRefGoogle Scholar
  3. 3.
    Erenpreisa J, Ivanov A, Wheatley SP, Kosmacek EA, Ianzini F, Anisimov AP, Mackey M, Davis PJ, Plakhins G, Illidge TM (2008) Endopolyploidy in irradiated p53-deficient tumour cell lines: persistence of cell division activity in giant cells expressing Aurora-B kinase. Cell Biol Int 32(9):1044–1056CrossRefGoogle Scholar
  4. 4.
    Sagona AP, Stenmark H (2010) Cytokinesis and cancer. FEBS Lett 584(12):2652–2661CrossRefGoogle Scholar
  5. 5.
    Nakayama Y, Igarashi A, Kikuchi I, Obata Y, Fukumoto Y, Yamaguchi N (2009) Bleomycin-induced over-replication involves sustained inhibition of mitotic entry through the ATM/ATR pathway. Exp Cell Res 315(15):2515–2528CrossRefGoogle Scholar
  6. 6.
    Xin L, Kang Y (2009) Cell fusion as a hidden force in tumor progression. Cancer Res 69(22):8536–8539CrossRefGoogle Scholar
  7. 7.
    Xin L, Kang Y (2009) Efficient acquisition of dual metastasis organotropism to bone and lung through stable spontaneous fusion between mda-mb-231 variants. Proc Natl Acad Sci 106(23):9385–9390CrossRefGoogle Scholar
  8. 8.
    Illidge TM, Cragg MS, Fringes B, Olive P, Erenpreisa JA (2000) Polyploid giant cells provide a survival mechanism for p53 mutant cells after DNA damage. Cell Biol Int 24(9):621–33CrossRefGoogle Scholar
  9. 9.
    Makarovskiy AN, Siryaporn E, Hixson DC, Akerley W (2002) Survival of docetaxel-resistant prostate cancer cells in vitro depends on phenotype alterations and continuity of drug exposure. Cell Mol Life Sci 59(7):1198–1211CrossRefGoogle Scholar
  10. 10.
    Ogden A, Rida PCG, Knudsen BS, Kucuk O, Aneja R (2015) Docetaxel-induced polyploidization may underlie chemoresistance and disease relapse. Cancer Lett 367(2):89–92CrossRefGoogle Scholar
  11. 11.
    Puig PE, Guilly MN, Bouchot A, Droin N, Cathelin D, Bouyer F, Favier L, Ghiringhelli F, Kroemer G, Solary E, Martin F, Chauffert B (2008) Tumor cells can escape DNA-damaging cisplatin through DNA endoreduplication and reversible polyploidy. Cell Biol Int 32(9):1031–1043CrossRefGoogle Scholar
  12. 12.
    Zhang S, Mercado-Uribe I, Hanash S, Liu J (2013) ITRAQ-based proteomic analysis of polyploid giant cancer cells and budding progeny cells reveals several distinct pathways for ovarian cancer development. PLoS ONE 8(11):1–16Google Scholar
  13. 13.
    Zhang S, Mercado-Uribe I, Xing Z, Sun B, Kuang J, Liu J (2014) Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene 33(1):116–128CrossRefGoogle Scholar
  14. 14.
    Lopez-Sánchez LM, Jimenez C, Valverde A, Hernandez V, Peñarando J, Martinez A, Lopez-Pedrera C, Muñoz-Castañeda JR, Juan R, Aranda E, Rodriguez-Ariza A (2014) CoCl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer. PLoS ONE 9(6):e99143CrossRefGoogle Scholar
  15. 15.
    Storchova Z, Pellman D (2004) From polyploidy to aneuploidy, genome instability and cancer. Nat Rev Mol Cell Biol 5(1):45–54CrossRefGoogle Scholar
  16. 16.
    Lin K, Torga G, Wu A, Rabinowitz JD, Murray WJ, Sturm JC, Pienta KJ, Austin R (2017) Epithelial and mesenchymal prostate cancer cell population dynamics on a complex drug landscape. Converg Sci Phys Oncol 3(4):045001CrossRefGoogle Scholar
  17. 17.
    Brabletz T, Kalluri R, Angela NM, Weinberg RA (2018) Emt in cancer. Nat Rev Cancer 18(2):128–134CrossRefGoogle Scholar
  18. 18.
    Roca H, Hernandez J, Weidner S, McEachin RC, Fuller D, Sud S, Schumann T, Wilkinson JE, Zaslavsky A, Li H, Maher CA, Daignault-Newton S, Healy PN, Pienta KJ (2013) Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer. PLoS ONE 8(10):e76773CrossRefGoogle Scholar
  19. 19.
    Kanda T, Sullivan KF, Wahl GM (1998) Histone-GFP fusion protein enables sensitive analysis of chromosome dynamics in living mammalian cells. Curr Biol 8(7):377–385CrossRefGoogle Scholar
  20. 20.
    Wottawah F, Schinkinger S, Lincoln B, Ananthakrishnan R, Romeyke M, Guck J, Kas J (2005) Optical rheology of biological cells. Phys Rev Lett 94(9):098103CrossRefGoogle Scholar
  21. 21.
    Long H, Xiang T, Qi W, Huang J, Chen J, He L (2015) Cancer cell metastasis via CCL5 induced epithelial–mesenchymal transition. Oncotarget 6(8):13–14CrossRefGoogle Scholar
  22. 22.
    Cioffi M, Dalterio C, Camerlingo R, Tirino V, Consales C, Riccio A, Ieranò C, Cecere SC, Losito NS, Greggi S, Pignata S, Pirozzi G, Scala S (2015) Identification of a distinct population of CD133+ CXCR4+ cancer stem cells in ovarian cancer. Sci Rep 5:1–11CrossRefGoogle Scholar
  23. 23.
    Lee HH, Bellat V, Law B (2017) Chemotherapy induces adaptive drug resistance and metastatic potentials via phenotypic CXCR4-expressing cell state transition in ovarian cancer. PLoS ONE 12(2):1–17Google Scholar
  24. 24.
    Axelrod R, Hamilton WD (1981) The evolution of cooperation. Science 211(4489):1390–1396CrossRefGoogle Scholar
  25. 25.
    Wu A, Zhang Q, Lambert G, Khin Z, Gatenby R, Kim HJ, Pourmand N, Bussey K, Davies PCW, Sturm JC, Austin RH (2015) Ancient hot and cold genes and chemotherapy resistance emergence. Proc Natl Acad Sci 112(33):10467–10472CrossRefGoogle Scholar
  26. 26.
    Han J, Jun Y, Kim SH, Hoang H, Jung Y, Kim S, Kim J, Austin RH, Lee S, Park S (2016) Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology. Proc Natl Acad Sci 113(50):14283–14288CrossRefGoogle Scholar
  27. 27.
    Bos J, Zhang Q, Vyawahare S, Rogers E, Rosenberg SM, Austin RH (2015) Emergence of antibiotic resistance from multinucleated bacterial filaments. Proc Natl Acad Sci 112(1):178–183CrossRefGoogle Scholar
  28. 28.
    Meads MB, Hazlehurst LA, Dalton WS (2008) The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin Cancer Res 14(9):2519–2526CrossRefGoogle Scholar
  29. 29.
    Shain KH, Dalton WS (2009) Environmental-mediated drug resistance: a target for multiple myeloma therapy. Expert Rev Hematol 2(6):649–662CrossRefGoogle Scholar
  30. 30.
    Nefedova Y, Cheng P, Alsina M, Dalton WS, Gabrilovich DI (2004) Involvement of notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood 103(9):3503–3510CrossRefGoogle Scholar
  31. 31.
    Mango RL, van Deventer HW, Wu QP, Serody JS (2009) Pulmonary stromal cells expressing cc-chemokine receptor 5 promote metastasis via erythroid differentiation regulator 1. Blood 114(22):3601–3601Google Scholar
  32. 32.
    Zarif JC, Taichman RS, Pienta KJ (2014) Tam macrophages promote growth and metastasis within the cancer ecosystem. OncoImmunology 3(7):e941734CrossRefGoogle Scholar
  33. 33.
    Reiman JM, Knutson KL, Radisky DC (2010) Immune promotion of epithelial–mesenchymal transition and generation of breast cancer stem cells. Cancer Res 70(8):3005–3008CrossRefGoogle Scholar
  34. 34.
    Coward J, Harding A (2014) Size does matter: why polyploid tumor cells are critical drug targets in the war on cancer. Front Oncol 4:123CrossRefGoogle Scholar
  35. 35.
    Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez J, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Princeton UniversityPrincetonUSA
  2. 2.Johns Hopkins Medical InstituteBaltimoreUSA
  3. 3.University of MichiganAnn ArborUSA

Personalised recommendations