Implicit in the clonal selection theory and its variants is the idea that cancer cells need to accumulate a sufficient number of genetic and epigenetic alterations to acquire full metastatic capacity, requiring that metastasis INCB018424 nmr is a rather late event during tumor progression to allow the accumulation of such alterations [30]. This notion is consistent with the generally accepted correlation between primary tumor size and risk of lymph node and distant metastasis [27], and the observation that metastatic genes are already expressed in primary tumors [31]. In the last few
years a significant body of evidence has emerged which indicates that tumor cells that ultimately form metastases may disseminate very early after tumorigenesis. This notion is based on the genomic analysis of single disseminated tumor cells (DTCs), as well as matched Regorafenib cell line primary tumors and their metastases from human patients [8] and [22]. Similarly, experimental manipulation of animal models of metastasis suggests that dissemination may occur even at pre-malignant stages of tumorigenesis [32]. Consistently, circulating
tumor cells (CTCs) in the blood and DTCs in the bone marrow can both be detected at early stages of tumor development in cancer patients [30], [33], [34], [35], [36] and [37]. To accommodate these observations, an alternative model has been proposed in which tumor cells disseminate early during tumor progression, and subsequently acquire additional genetic changes that ultimately allow them to grow out as metastases at the distant site. In this model, primary tumors and metastases progress in parallel as independent lesions [8]. Clonal selection in primary tumors and metastases would be compatible with this model, but would not be a pivotal determinant of when dissemination of the metastatic seed occurs.
The comparative genomic analysis of DTCs from lymph node and bone and their corresponding primary tumors has been performed using Substrate-level phosphorylation comparative genomic hybridization (CGH) for a number of types of cancer, and provides significant evidence in support of a parallel progression model. For example, DTCs generally show fewer genetic abnormalities than their primary tumors and there is also extensive disparity between chromosomal gains and losses when DTCs and their primary tumors are compared (reviewed in [8] and [22]). These studies also provide evidence that genetic abnormalities in DTCs were acquired independently of those in the primary tumor, and that substantial numbers of chromosomal losses were found in primary tumors that were not present in DTCs. As loss of DNA is irreversible and transmitted to progeny, these observations provide evidence for both early dissemination of metastatic founder cells and parallel progression.