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Differentiation genes: are they primary targets for human carcinogenesis?

K N Prasad1, A R Hovland, P Nahreini

  • 1Center for Vitamins and Cancer Research, Department of Radiology, School of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA. kedar.prasad@uchsc.edu

Experimental Biology and Medicine (Maywood, N.J.)
|September 25, 2001
PubMed

Insights

Cancer initiation may stem from the loss of differentiation genes, not oncogene mutations. This hypothesis suggests differentiation gene downregulation is the primary event in human carcinogenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Identifying primary targets in human carcinogenesis remains challenging.
  • Mutated oncogenes or growth regulatory genes typically fail to immortalize or transform normal human epithelial cells, suggesting they are secondary events.
  • Existing research suggests gene downregulation, specifically of differentiation genes, may be the primary event.

Purpose of the Study:

  • To propose a novel hypothesis for human carcinogenesis.
  • To identify potential primary targets in cancer development.
  • To differentiate between tumor-initiating and tumor-promoting genes.

Main Methods:

  • Review of experimental studies on molecular carcinogenesis.
  • Analysis of gene function in cellular transformation and immortalization.
  • Examination of differentiation induction in neuroblastoma (NB) cells using adenosine 3',5'-cyclic monophosphate (cAMP).

Main Results:

  • Downregulation of a differentiation gene, termed a tumor-initiating gene, is hypothesized as the primary event in carcinogenesis.
  • This downregulation can occur via mutation, activation of suppressor genes, or inactivation of tumor suppressor genes, leading to cell immortalization.
  • Subsequent mutations in proto-oncogenes or growth regulatory genes in immortalized cells drive transformation, identifying them as tumor-promoting genes.
  • Experiments with NB cells and cAMP support the hypothesis, showing that differentiation can be induced, but resistance indicates mutations or unresponsive regulatory genes.
  • The hypothesis is applicable to various cancers including melanoma, glioma, and colon cancer.

Conclusions:

  • The primary event in human carcinogenesis may be the downregulation of a differentiation gene (tumor-initiating gene).
  • Cellular transformation occurs in subsequent steps involving tumor-promoting genes.
  • This model provides a new framework for understanding carcinogenesis and identifying therapeutic targets.

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