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PMID: 9062390 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Influence of the host microenvironment on the clonal selection of human colon carcinoma cells during primary tumor growth and metastasis.

Clinical & experimental metastasis ·Vol. 15 ·No. 2 ·1997-03-00 ·Pages 140-50

Singh RK, Tsan R, Radinsky R

Abstract

The purpose of this study was to determine the subpopulation dynamics of human colon carcinoma (HCC) cells growing at orthotopic (cecum, liver) or ectopic (subcutis, kidney, spleen) sites in nude mice and to correlate any outgrowth of distinct clones with the differential expression of metastasis-related genes. Low metastatic KM12C HCC cells were genetically tagged with a retrovirus harboring the neomycin-resistance (Neo(R)) gene. Southern blot analyses demonstrated only minor resolution of the Neo(R) hybridization pattern in DNA isolated from primary tumors growing orthotopically or ectopically, suggesting a polyclonal outgrowth. In contrast, a major resolution of the Neo(R) hybridization pattern was observed in liver-specific metastases, demonstrating the outgrowth of single dominant clones. Expression of epidermal growth factor receptor (EGR-R) increased 20-60% in the liver metastases vs spleen tumors and the KM12C Neo(R) cells. Transforming growth factor alpha (TGF-alpha), amphiregulin (AR), and c-met showed only modest differences in mRNA expression. A 20-80% increase in type IV collagenase mRNA levels was also observed in all tumor specimens. Furthermore, expression of the multi-drug resistance gene PGY-1 and the carcinoembryonic antigen (CEA) gene were elevated in the liver metastases compared with the spleen tumors and cultured cells. Transcript levels of the angiogenic factors interleukin-8 and basic fibroblast growth factor did not correlate with clonal outgrowth. These data demonstrate a correlation between EGF-R, type IV collagenase, CEA, and PGY-1 gene expression and the production of liver metastases. Our results suggest that distinct HCC clones differentially expressing specific mRNA transcripts for metastasis-related genes are the forerunners of the experimental liver metastatic lesions.

MeSH Terms
Animals Blotting, Southern Carcinoembryonic Antigen/metabolism Colonic Neoplasms/genetics,metabolism,pathology Drug Resistance, Multiple/genetics ErbB Receptors/metabolism Genes, Reporter Genetic Vectors Humans Liver Neoplasms/genetics,metabolism,secondary Male Mice Mice, Nude Neomycin Neoplasm Proteins/metabolism Organ Specificity Proto-Oncogene Proteins c-met RNA, Messenger/metabolism Receptor Protein-Tyrosine Kinases/metabolism Retroviridae
Chemicals
Carcinoembryonic Antigen Neoplasm Proteins RNA, Messenger ErbB Receptors Proto-Oncogene Proteins c-met Receptor Protein-Tyrosine Kinases Neomycin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Singh R K
Department of Cell Biology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Tsan R
Radinsky R
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Article Info
Journal
Clinical & experimental metastasis
Abbr.
Clin Exp Metastasis
ISSN
0262-0898
DOI
10.1023/a:1018400826845
Published
1997-03-00
Pages
140-50
Language
English
Region
Netherlands
NLM ID
8409970
Subset
IM
Grants
NCI NIH HHS · R29-CA67952 · United States
External Links
PubMed source DOI: 10.1023/a:1018400826845 View journal details
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