Unknown Primary Tumors: An Example of Accelerated (Type 2) Tumor Progression

Abstract

The acquisition of the malignant phenotype (invasiveness and metastasis) by tumor cells has been attributed to tumor progression, a term used by Foulds to describe the acquisition of permanent irreversible changes in a neoplasm¹. Progression in turn has generally been presumed to result from “genetic instability” that results in the emergence of neoplastic cells that have lost control of the mechanisms governing or regulating gene expression^2,3. From these ideas evolved the proposal that tumor progression is generally unidirectional, since genetic or genomic changes favoring malignant cells with some form of a presumed growth advantage generally come to dominate tumor growth. The advantages acquired by these cells were hypothesized to be due to an increasing rate of genomic instability that accompanied the increasingly malignant phenotype^4,5. Thus, it is believed that only cells with an increased rate of genomic instability become malignant (metastatic). In short the transformation of normal cells into tumor cells is thought to be accompanied by the destabilization of the genome, leading to tumor heterogeneity which in turn accompanies tumor progression to a malignant phenotype. One difficulty with this paradigm is that we have only a minimal understanding of the events responsible for the transformation of a normal to a malignant cell. It has therefore been accepted a priori that any analysis of tumor initiation, promotion and progression accept this gap in knowledge and proceed from there.

Supported in part by Grant number 38953 from the PHS and Cancer Development Funds of The University of Texas M. D. Anderson Cancer Center