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

Rakesh K Singh, Rachel Tsan, Robert Radinsky

Research output: Contribution to journalArticle

45 Citations (Scopus)

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-α), 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.

Original languageEnglish (US)
Pages (from-to)140-150
Number of pages11
JournalClinical and Experimental Metastasis
Volume15
Issue number2
DOIs
StatePublished - Apr 23 1997

Fingerprint

Colon
Neomycin
Neoplasm Metastasis
Carcinoma
Liver
Growth
Neoplasms
Spleen
Clone Cells
Genes
Carcinoembryonic Antigen
Collagenases
Messenger RNA
Cultured Tumor Cells
Transforming Growth Factor alpha
Cecum
Angiogenesis Inducing Agents
Multiple Drug Resistance
Fibroblast Growth Factor 2
Retroviridae

Keywords

  • growth factors
  • liver metastasis
  • molecular mechanisms
  • protein tyrosine kinase receptors

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Influence of the host microenvironment on the clonal selection of human colon carcinoma cells during primary tumor growth and metastasis. / Singh, Rakesh K; Tsan, Rachel; Radinsky, Robert.

In: Clinical and Experimental Metastasis, Vol. 15, No. 2, 23.04.1997, p. 140-150.

Research output: Contribution to journalArticle

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