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 journalArticlepeer-review

46 Scopus citations


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
Issue number2
StatePublished - 1997


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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Influence of the host microenvironment on the clonal selection of human colon carcinoma cells during primary tumor growth and metastasis'. Together they form a unique fingerprint.

Cite this