Skip to main content
SpringerLink
Log in

EGF receptor signaling enhances in vivo invasiveness of DU-145 human prostate carcinoma cells

  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Carcinomas of the prostate and other lineages often present an autocrine stimulatory loop acting via the EGF receptor (EGFR). We have recently shown that EGFR-mediated signals enhance DU-145 prostate carcinoma cell transmigration of an extracellular matrix in vitro, and that this increased invasiveness was independent of proteolytic degradation of the matrix (Xie et al., 1995, Clin Exp Metastasis, 13, 407). To determine whether up-regulated EGFR signaling promotes tumor progression in vivo and to define the EGFR-induced cell property responsible, we inoculated athymic mice with genetically-engineered DU-145 cells. Parental DU-145 cells and those transduced to overexpress a full-length wild type (WT) EGFR formed tumors and metastasized to the lung when inoculated in the prostate and peritoneal cavity. The WT DU-145 tumors were more invasive. DU-145 cells expressing a mitogenically-active, but motility-deficient (c'973) EGFR formed small, non-invasive tumors without evidence of metastasis. All three sublines demonstrated identical, EGFR-dependent rates of cell growth in vitro, suggesting that the differential invasiveness was not due to altered growth rates. To determine whether cell motility may be, in part, responsible for tumor invasiveness, we treated WT DU-145 intraperitoneal tumors with a pharmacologic agent (U73122) which blocks EGFR-mediated cell motility but not mitogenesis. Under this treatment regimen, the WT DU-145 cells formed tumors of similar numbers and size to those formed without treatment; however, these tumors were much less invasive. These data suggest that EGFR-mediated cell motility is an important mechanism involved in tumor progression, and that this cell property may represent a novel target to limit the spread of tumors.

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

Similar content being viewed by others

References

  1. Partin AW and Coffey DS, 1994, Benign and Malignant Prostatic Neoplasms: human studies. San Diego, California: Academic Press.

    Google Scholar 

  2. Sandberg AA, 1992, Cytogenetic and Molecular Genetic Aspects of Human Prostate Cancer: primary and metastatic. New York: Plenum Press.

    Google Scholar 

  3. Geldof AA and Rao BR, 1990, Factors in prostate cancer metastasis. Anticancer Res, 10, 1303–6.

    Google Scholar 

  4. Linehan WM, 1995, Inhibition of prostate cancer metastasis: a critical challenge ahead. J Natl Cancer Inst, 87, 331–2.

    Google Scholar 

  5. Gittes RF, 1991, Carcinoma of the prostate. N Engl J Med, 324, 236–45.

    Google Scholar 

  6. Surya BV and Provet JA, 1989, Manifestations of advanced prostate cancer: prognosis and treatment. J Urol, 142, 921–8.

    Google Scholar 

  7. McKeehan WL, 1986, Growth factors spawn new cell cultures. Nature, 321, 629–30.

    Google Scholar 

  8. Chaproniere DM and Webber MM, 1985, Dexamethasone and retinyl acetate similarly inhibit and stimulate EGF or insulin-induced proliferation of prostatic epithelium. J Cell Physiol, 122, 249–53.

    Google Scholar 

  9. Eaton CL, Davies P and Phillips MEA, 1988, Growth factor involvement and oncogene expression in prostatic tumors. J Ster Biochem, 30, 341–5.

    Google Scholar 

  10. Marti U, Burwen SJ and Jones AL, 1989, Biological effects of epidermal growth factor, with emphasis on the gastrointestinal tract and liver: an update. Hepatology, 9, 126–38.

    Google Scholar 

  11. Connolly JM and Rose DP, 1989, Secretion of epidermal growth factor and related polypeptides by the DU 145 human prostate cancer cell line. Prostate, 15, 177–86.

    Google Scholar 

  12. Nishi N, Matuo Y and Wada F, 1988, Partial purification of a major type of rat prostatic growth factor: characterization as an epidermal growth factor-related mitogen. Prostate, 13, 209–20.

    Google Scholar 

  13. Wilding G, Valverius E, Knabbe C and Gelmann EP, 1989, Role of transforming growth factor-α in human prostate cancer cell growth. Prostate, 15, 1–12.

    Google Scholar 

  14. Liu X-H, Wiley HS and Meikle AW, 1993, Androgens regulate proliferation of human prostate cancer cells in culture by increasing transforming gowth factor-α (TGF-α) and epidermal growth factor (EGF)/TGF-α receptor. J Clin Endocr Metab, 77, 1472–8.

    Google Scholar 

  15. Aaronson SA, 1991, Growth factors and cancer. Science, 254, 1146–53.

    Google Scholar 

  16. Schlegel J, Merdes A, Stumm G, et al., 1994, Amplification of the epidermal growth factor receptor gene correlates with different growth behavior in human glioblastoma. Int J Cancer, 56, 72–7.

    Google Scholar 

  17. Collins VP, 1993, Amplified genes in human gliomas. Sem Cancer Biol, 4, 27–32.

    Google Scholar 

  18. Yasui W, Sumiyoshi H, Hata J, et al., 1988, Expression of epidermal growth factor receptor in human gastric and colon carcinomas. Cancer Res, 48, 137–41.

    Google Scholar 

  19. Neal DE, Marsh C, Bennett MK, et al., 1985, Epidermal-growth-factor receptors in human bladder cancer: comparison of invasive and superficial tumours. Lancet, i, 366–8.

    Google Scholar 

  20. Nguyen PL, Swanson PE, Jaszcz W, et al., 1994, Expression of epidermal growth factor receptor in invasive transitional cell carcinoma of the urinary bladder: a multivariate survival analysis. Am J Clin Pathol, 101, 166–76.

    Google Scholar 

  21. Klijn JG, Berns PM, Schmitz PI and Foekens JA, 1992, The clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: a review on 5232 patients. Endocr Rev, 13, 3–17.

    Google Scholar 

  22. Sainsbury JRC, Farndon JR, Needham GK, Malcolm AJ and Harris AL, 1987, Epidermal-growth-factor receptor status as predictor of early recurrence of and death from breast cancer. Lancet, i, 1398–402.

    Google Scholar 

  23. Radinsky R, Risin S, Fan D, et al., 1995, Level and function of epidermal growth factor receptor predict the metastatic potential of human colon carcinoma cells. Clin Cancer Res, 1, 19–31.

    Google Scholar 

  24. Lubrano C, Petrangeli E, Catizone A, et al., 1989, Epidermal growth factor binding and steroid receptor content in human benign prostatic hyperplasia. J Ster Biochem, 34, 499–504.

    Google Scholar 

  25. Morris GL and Dodd JG, 1990, Epidermal growth factor receptor mRNA levels in human prostatic tumors and cell lines. J Urol, 143, 1272–4.

    Google Scholar 

  26. Davies P and Eaton CL, 1989, Binding of epidermal growth factor by human normal, hypertrophic, and carcinomatous prostate. Prostate, 14, 123–32.

    Google Scholar 

  27. Myers RB, Kudlow JE and Grizzle WE, 1993, Expression of transforming growth factor alpha, epidermal growth factor and the epidermal growth factor receptor in adenocarcinoma of the prostate and benign prostatic hyperplasia. Modern Pathol, 6, 733–7.

    Google Scholar 

  28. Ching KZ, Ramsey E, Pettigrew N, D'Cunha R, Jason M and Dodd JG, 1993, Expression of mRNA for epidermal growth factor, transforming growth factor alpha and their receptor in human prostate tissue and cell lines. Molec Cell Biochem, 126, 151–8.

    Google Scholar 

  29. Tillotson JK and Rose DP, 1991, Endogenous secretion of epidermal growth factor peptides stimulates growth of DU145 prostate cancer cells. Cancer Lett, 60, 109–12.

    Google Scholar 

  30. Haugen DRF, Akslen LA, Varhaug JE and Lillehaug JR, 1993, Demonstration of a TGF-a-EGF-receptor autocrine loop and c-myc protein over-expression in papillary thyroid carcinomas. Int J Cancer, 55, 37–43.

    Google Scholar 

  31. Hamada J, Nagayasu H, Takayama M, Kawano T, Hosokawa M and Takeichi N, 1995, Enhanced effect of epidermal growth factor on pulmonary metastasis and in vitro invasion of rat mammary carcinoma cells. Cancer Lett, 89, 161–7.

    Google Scholar 

  32. Chakrabarty S, Rajagopal S and Huang S, 1995, Expression of antisense epidermal growth factor receptor RNA downmodulates the malignant behavior of human colon cancer cells. Clin Exp Metastasis, 13, 191–5.

    Google Scholar 

  33. Korc M, Chandrasekar B, Yamanaka Y, et al., 1992, Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J Clin Invest, 90, 1352–60.

    Google Scholar 

  34. Stone K, Mickey DD, Wunderli H, Mickey GH and Paulson DF, 1978, Isolation of a human prostate carcinoma cell line (DU145). Int J Cancer, 21, 274–81.

    Google Scholar 

  35. Connolly JM and Rose DP, 1992, Interactions between epidermal growth factor-mediated autocrine regulation and linoleic acid-stimulated growth of a human prostate cancer cell line. Prostate, 20, 151–8.

    Google Scholar 

  36. Xie H, Turner T, Wang M-H, Singh RK, Siegal GP and Wells A, 1995, In vitro invasiveness of DU-145 human prostate carcinoma cells is modulated by EGF receptor-mediated signals. Clin Exp Metastasis, 13, 407–19.

    Google Scholar 

  37. Chen P, Gupta K and Wells A, 1994, Cell movement elicited by epidermal growth factor receptor requires kinase and autophosphorylation but is separable from mitogenesis. J Cell Biol, 124, 547–55.

    Google Scholar 

  38. Chen P, Xie H, Sekar MC, Gupta KB and Wells A, 1994, Epidermal growth factor receptor-mediated cell motility: phospholipase C activity is required, but MAP kinase activity is not sufficient for induced cell movement. J Cell Biol, 127, 847–57.

    Google Scholar 

  39. Bleasdale JE, Thakur NR, Gremban RS, et al., 1990, Selective inhibition of receptor-coupled phospholipase C-dependent processes in human platelets and polymorphonuclear neutrophils. J Pharm Exp Ther, 255, 756–68.

    Google Scholar 

  40. Powis G, Seewald MJ, Gratas C, Melder D, Riebow J and Modest EJ, 1992, Selective inhibition of phosphatidylinositol phospholipase C by cytotoxic ether lipid analogues. Cancer Res, 52, 2835–40.

    Google Scholar 

  41. Wells A, Welsh JB, Lazar CS, Wiley HS, Gill GN and Rosenfeld MG, 1990, Ligand-induced transformation by a non-internalizing EGF receptor. Science, 247, 962–4.

    Google Scholar 

  42. Ullrich A, Coussens L, Hayflick JS, et al., 1984, Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature, 307, 418–25.

    Google Scholar 

  43. Welsh JB, Gill GN, Rosenfeld MG and Wells A, 1991, A negative feedback loop attenuates EGF-induced morphological changes. J Cell Biol, 114, 533–43.

    Google Scholar 

  44. Masui H, Wells A, Lazar CS, Rosenfeld MG and Gill GN, 1991, Enhanced tumorigenesis of NR6 cells which express non-downregulating epidermal growth factor receptors. Cancer Res, 51, 6170–5.

    Google Scholar 

  45. Service NTI, 1981–82, Registry of Toxic Effects of Chemical Substance. Washington DC: US Department of Commerce.

    Google Scholar 

  46. Peterson G and Barnes S, 1993, Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation. Prostate, 22, 335–45.

    Google Scholar 

  47. Knox JD, Mack CF, Powell WC, Bowden GT and Nagle RB, 1993, Prostate tumor cell invasion: a comparison of orthotopic and ectopic models. Invasion and Metastasis, 13, 325–31.

    Google Scholar 

  48. Powell WC, Knox JD, Navre M, et al., 1993, Expression of the metalloproteinase matrilysin in DU145 cells increases their invasive potential in severe combined immunodeficient mice. Cancer Res, 53, 417–22.

    Google Scholar 

  49. Sunada H, Magun BE, Mendelsohn J and MacLeod CL, 1986, Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation. Proc Natl Acad Sci, USA, 83, 3825–9.

    Google Scholar 

  50. Chen P, Xie H and Wells A, 1996, Mitogenic signaling from the EGF receptor is attenuated by a motility-associated phospholipase C-γ/protein kinase C feedback mechanism. Molec Biol Cell, 7, in press.

Download references

Author information

Authors and Affiliations

  1. Pathology and Laboratory Medicine Service, Birmingham Veterans Administration Medical Center, Birmingham, AL

    Alan NWells

  2. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    Timothy Turnert, Philip Chen & Lyndon J. Goodly

Authors
  1. Timothy Turnert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lyndon J. Goodly
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alan NWells
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan NWells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Turnert, T., Chen, P., Goodly, L.J. et al. EGF receptor signaling enhances in vivo invasiveness of DU-145 human prostate carcinoma cells. Clin Exp Metast 14, 409–418 (1996). https://doi.org/10.1007/BF00123400

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00123400

Keywords

Search

Navigation