Critical Determinants of Human Colon Cancer Metastasis

  • Isaiah J. Fidler


By the time of diagnosis, human colorectal carcinomas are heterogeneous and contain a large number of subpopulations of cells with diverse biological properties that include invasion and metastasis. The tumor cell heterogeneity is directed by both genetic and epigenetic events and may also be modulated by cell-to-cell interactions and tissue microenvironments. To produce metastasis, tumor cells must complete a series of sequential, interrelated, selective steps that include growth, vascularization, invasion into host stroma and entrance into the circulation, survival in the circulation and adhesion to capillary endothelial cells, extravasation into the organ parenchyma, response to local growth factors, proliferation, and induction of vascularization. All of these sequential steps must be completed by tumor cells if a metastasis is to develop. Although some of the steps in this process contain stochastic elements, metastasis as a whole favors the survival and growth of a few subpopulations of tumor cells that preexist within the heterogeneous parent neoplasm. Metastases can have a clonal origin, and different metastases can originate from the proliferation of single cells. Because each of the discrete steps in the pathogenesis of a metastasis is regulated by one or several independent genes, the identification of cells with metastatic potential in heterogeneous primary human tumors requires multiparametric— multivariate analysis of gene expression The pathogenesis of metastasis depends on multiple favorable interactions of metastatic cells with host homeostatic mechanisms. Interruption of one or more of these interactions can lead to the inhibition or eradication of cancer metastasis. For many years, all of our efforts to treat cancer have concentrated on the inhibition or destruction of tumor cells. The recent advancements in our understanding of the biologic basis of cancer metastasis recommend that metastases could be eradicated by both treatment of the tumor cells and modulation of the host environment.

The major cause of death from colonic or rectal carcinoma is metastases that are resistant to conventional therapy [1]. For this reason, once colon cancer is diagnosed, the urgent question is whether the cancer is localized or has already spread to the regional lymph nodes and distant organs. The major obstacle to treatment of metastasis is the biologic heterogeneity of neoplasms. By the time of diagnosis, a malignant tumor contains multiple cell populations with various properties, such as growth rate, karyotype, cell surface properties, antigenicity, immunogenicity, marker enzymes, sensitivity to various cytokines and cytotoxic drugs, and the ability to invade and produce metastasis [1–6]. A second obstacle to therapy is the finding that different organ environments can modify a metastatic tumor cell’s response to therapy [7, 8]. Understanding the mechanisms responsible for the development of biologic heterogeneity in primary cancers and metastases and the process by which tumor cells invade local tissues and spread to distant organs is a primary goal of cancer research. A better understanding of these processes should allow the design of more effective therapy for colon cancer and improvements in the way oncologists deal with disseminated cancer. In this chapter, I review recent data on the biology of human colon cancer metastasis and the host factors that influence this process


Epidermal Growth Factor Receptor Nude Mouse Human Colon Natl Cancer Inst Metastatic Cell 
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Copyright information

© Springer Japan 1997

Authors and Affiliations

  • Isaiah J. Fidler
    • 1
  1. 1.Department of Cell Biology, M. D. Anderson Cancer CenterThe University of TexasHoustonUSA

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