Abstract
LacZ-tagged human prostate carcinoma CWR22Rv1 cells metastasize spontaneously to lung, liver, and bone from subcutaneous primary tumors in athymic nude mice; these organs are ‘natural’ targets of metastasis for the human disease. To evaluate the mechanism(s) of metastasis to these organs, an experimental metastasis model was used by taking advantage of the ultrasensitive detection of lacZ. Within 1 h after tail vein injection, micrometastases were forming in lung, liver, bone, kidney, and brain with very different quantitative levels. The kinetics of loss of unstable micrometastases and retention of stable ones were also very different in these organs. After injecting suspensions of single cells, both whole-organ and serial-section staining for lacZ revealed considerable heterogeneity in cell number of individual lung micrometastases while micrometastases in liver contained only 1 or 2 cells. The size of individual bone micrometastases also suggested only 1 or 2 cells. Tumor cells could also be detected in the small blood vessels of the lung within minutes after injection. These studies indicate that lacZ-tagged CWR22Rv1 cells after tissue culturing contain subsets of cells capable of establishing transient micrometastases in lung, liver, and bone after direct injection into the animal’s circulation. Moreover, the quantitative and qualitative properties of the micrometastases in the three organs differ significantly, suggesting different mechanisms for stabilization and fates of micrometastases in these organs.
Similar content being viewed by others
References
Pretlow TG, Pelley RJ, Pretlow, TP. Biochemistry of prostatic carcinoma. In Pretlow TG II and Pretlow TP (eds): Biochemical and Molecular Aspects of Selected Cancers, Vol 2. San Diego, California: Academic Press 1994; 169–237.
Zhau H YE, Chang S-M, Chen B-Q et al. Androgen-repressed phenotype in human prostate cancer. Proc Natl Acad Sci USA 1996; 93: 15152–7.
Lalani E-N, Lanaido ME and Abel PD.Molecular and cellular biology of prostate cancer. Cancer Met Rev 1997; 16:29–66.
Rubio N, Villacampa, MM, Blanco J. Traffic to lymph nodes of PC-3 prostate tumor cells in nude mice visualized using the luciferase gene as a tumor cell marker. Lab Invest 1998; 78:1315–25.
Wu TT, Sikes RA, Cui Q et al. Establishing human prostate cancer cell xenografts in bone: Induction of osteoblastic reaction by prostate-specific antigen-producing tumors in athymic and SCID/bg mice using LNCaP and lineage-derived metastatic sublines.Int J Cancer1998; 77:887–94.
Yang M Jiang, P Sun, F-X et al. A fluorescent orthotopic bone metastasis model of human prostate cancer. Cancer Res 1999; 59: 781–6.
Pretlow TG, Wolman SR, Micale MA et al. Xenografts of primary human prostatic carcinoma. J Natl Cancer Inst 1993; 85: 394–8.
Wainstein MA, He F, Robinson D et al. CWR22: Androgen-dependent xenograft model derived from a primary human prostatic carcinoma. Cancer Res 1994;54: 6049–52.
Cheng L, Sun J, Pretlow TG et al. CWR22 xenograft as an ex vivo human tumor model for prostate cancer gene therapy. J Natl Cancer Inst 1996;88:607–11.
Nagabhushan M, Miller CM, Pretlow TP et al. CWR22: the first human prostate cancer xenograft with strongly androgen-dependent and relapsed strains both in vivo and in soft agar.Cancer Res 1996; 56: 3042–46.
Sramkoski RM, Pretlow TG, Giaconia JM et al. A new human prostate carcinoma cell line, 22Rv1. In Vitro 1999;35: 403–9.
Holleran JL, Miller CJ, Culp LA. Tracking micrometastasis to multiple organs with lacZ-tagged CWR22R prostate carcinoma cells.J Histochem Cytochem 2000; 48: 643–51.
Lin W-C, Culp LA. New insights into micrometastasis development using ultrasensitive marker genes. In Spandidos DA (ed): Current Perspectives on Molecular and Cellular Oncology, Vol 1, Part B. London: JAI Press: 1992; 261–309.
Culp LA, Lin W-C, Kleinman NR et al. Earliest steps in primary tumor formation and micrometastasis resolved with histochemical markers of gene-tagged tumor cells. J Histochem. Cytochem 1998; 46: 557–67.
Culp LA, Lin W-C, Kleinman NR et al. Tumor progression, micrometastasis, and genetic instability tracked with histochemical marker genes.Progr Histochem Cytochem1998;33: 329–50.
Kruger A, Schirrmacher V, Khokha R. The bacterial lacZ gene: An important tool for metastasis research and evaluation of new cancer therapies.Cancer Met Rev1999;17:285–94.
Chang C-M, Chung LWK. Interaction between prostatic fibroblast and epithelial cells in culture: Role of androgen.Endocrinology1989; 125:2719–27.
Yang M, Baranov E, Li X-M et al. Whole-body and intravital optical imaging of angiogenesis in orthotopically implanted tumors.Proc Natl Acad Sci USA 2001;98:2616–21.
Hoffman RM. Visualization of GFP-expressing tumors and metastasis in vivo.BioTechniques 2001;30: 1016–26.
Lin W-C, Pretlow TP, Pretlow TG et al.Development of micrometastases: earliest events detected with bacterial lacZ gene-tagged tumor cells.J Natl Cancer Inst1990;82:1497–503.
Lin W-C, O’Connor KL, Culp LA. Complementation of two related tumor cell classes during experimental metastasis tagged with different histochemical marker genes.Br J Cancer1993;67:910–21.
Lin W-C, Culp LA. Altered establishment/clearance mechanisms during experimental micrometastasis with live and/or disabled bacterial lacZ-tagged tumor cells.Invasion and Metastasis 1992;12:197–209.
Kleinman NR, Lewandowska K, Culp LA. Tumour progression of human neuroblastoma cells tagged with a lacZ marker gene: earliest events at ectopic injection sites.Br J Cancer 1994;69:670–9.
Fidler IJ, Hart IR. Biological diversity in metastatic neoplasms: origins and implications.Science 1982; 217:998–1003.
Nicolson GL. Cancer metastasis: Tumor cell and host organ properties important in metastasis to specific secondary sites.Biochim Biophys Acta1998;948:175–224.
Nicolson GL. Tumor and host molecules important in the organ preference of metastasis.Semin Cancer Biol 1991;2:143–54.
Nicolson GL. Cancer progression and growth: relationship of paracrine and autocrine growth mechanisms to organ preference of metastasis.Exp Cell Res 1993; 204: 171–80.
Fu X, Herrera H, Hoffman RM. Orthotopic growth and metastasis of human prostate carcinoma in nude mice after transplantation of histologically intact tissue.Int J Cancer 1992;52:987–90.
Sato H, Gleave ME, Bruchovsky N et al. A metastatic and androgensensitive human prostate cancer model using intraprostatic inoculation of LNCaP cells in SCID mice. Cancer Res 1997; 57:1584–89.
Stephenson RA, Dinney CPN, Gohji K et al. Metastatic model for human prostate cancer using orthotopic implantation in nude mice.J Natl Cancer Inst 1992; 84:951–7.
Emmert-Buck MR, Bonner RF, Smith PD et al. Laser capture microdissection. Science 1996; 274:998–1001.
Schutze K, Lahr G. Identification of expressed genes by lasermediated manipulation of single cells.Nature Biotechnol 1998;16: 737–42.
Simone NL, Bonner RF, Gillespie JW et al. Laser-capture microdissection: opening the microscopic frontier to molecular analysis. Trends Genetics 1998; 14: 272–6.
Fisher B, Fisher ER.The organ distribution of disseminated 51Crlabeled tumor cells.Cancer Res 1967;27:412–20.
Fidler IJ. Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125I-5-iodo-2′-deoxyuridine.J Natl Cancer Inst1970;45:773–82.
Tarin D, Price JE. Influence of microenvironment and vascular anatomy on ‘metastatic’ colonization potential of mammary tumors. Cancer Res 1981; 41:3604–9.
Fornabaio DM, Alterman AL, Stackpole CW. Metastatic dissemination of B16 melanoma: Evidence that metastases can result from nonspecific trapping of disseminated tumor cells.Invasion Metastasis 1988; 8: 1–16.
Aslakson CJ, McEachern D, Conaway DH et al. Inhibition of lung colonization at two different steps in the metastatic sequence.Clin Exp Metastasis 1991;9: 139–50.
Glaves D. Metastasis: reticuloendothelial system and organ retention of disseminated malignant cells.Int J Cancer 1980; 26:115–22.
Ramani P, Blackwill FR. Human interferons inhibit experimental metastases of a human melanoma cell line in nude mice.Br J Cancer 1988;58:350–4.
Barlozzari T, Reynolds CW, Herberman RB. In vivo role of natural killer cells: involvement of large granular lymphocytes in the clearance of tumor cells in anti-asialo GM1-treated rats.J Immunol 1983; 131:1024–7.
Weiss L, Dimitrov DS, Angelova M. The hemodynamic destruction of intravascular cancer cells in relation to myocardial metastasis. Proc Natl Acad Sci USA 1985;82: 5737–41.
Kawaguchi T, Nakamura K. Analysis of the lodgement and extravasation of tumor cells in experimental models of hematogeneous metastasis.Cancer Metastasis Rev 1986; 5:77–94.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Holleran, J.L., Miller, C.J., Edgehouse, N.L. et al. Differential experimental micrometastasis to lung, liver, and bone with lacZ-tagged CWR22R prostate carcinoma cells. Clin Exp Metastasis 19, 17–24 (2002). https://doi.org/10.1023/A:1013833111207
Issue Date:
DOI: https://doi.org/10.1023/A:1013833111207