A New Model Of Tumor Metastatic Progression And Preliminary Analysis

Metastasis is the most lethal attribute of a cancer. However,the metastatic progression of solid tumors is still unclear. A generally accepted model is the clonal evolution model. This model suggests that the metastasis is a clonally selective process . Finally one subclone in primary tumor acquires the full metastasis capacity and gives rise to a metastatic tumor. In this model,metastasis represents the end stage of evolution. The occurrence of bone micrometastases early in the evolution of cancer and the presence of metastasis genes in gene-expression signatures of primary tumors would seem to challenge this traditional model.In early-stage breast cancer without manifest metastasis,malignant cells (M0 cells) in bone marrow and other sites can show substantial genetic differences compared not only with the primary tumor,but also with each other,suggesting early dissemination and parallel evolution (the parallel evolution model) . However,M1 cells from patients with manifest metastasis were found to be less heterogeneous than M0 cells. This result would seem to contradict the parallel evolution model.In addition,many of genes associated with metastatic virulence do not give the primary tumor a selective advantage,and thus they would not be represented in gene signatures of the primary tumor,because that metastatic cells would be too rare to influence a population-averaged gene-expression profile of the primary tumor. The presence of metastasis genes in gene-expression signatures of primary tumors led to the proposal of the same gene model. This same gene model holds that there are various types of primary tumor,some of which are preordained to become metastatic,others not. Taking into account the continued evolution,these primary tumors preordained not to metastatic could acquire the full metastasis capacity. We don't think that the same gene model can perfectly interpret the presence of metastasis genes in primary tumors.Norton L proposed that cancer is a disease of self-seeding. Cancer cell departed from primary or metastatic sites might seed into primary site. Cancer cells spread early from the primary site even before onset of chromosomal instability. The early-disseminated cancer cells may give rise to metastasis. Logically,cancer cell may depart from the metastatic site early. If the cells can migrate between primary cite and metastatic sites and given adequate time,finally the clone with most selective advantage would dominate the primary and metastatic sites. Of course this clone could originate from primary or metastatic sites. Therefore,we surmise that the metastasis progression is a clonally selective process on whole-body level. The main differences between our model and the other models are whether or not to think about the interaction between primary and second cancer. Our hypothesis might provide a novel explanation for contradictory results of compare between primary cancers and their metastases'gene expression profiles. Cancer cells at early-stage of cancer were genetically distinct from the matched primary tumors,but bone marrow–derived cancer cells in patients with overt metastatic disease were less genetically disparate. This finding may reflect differences between the phases of evolution. In the last phase,one clone dominates the whole cancer including of the primary and metastatic cancer. Of course the metastasis genes can present in gene-expression signatures of primary cancers.This new model may not affect only the current view on progression of cancer but may also have some important clinical implications. The cancer cells are in a state of dormancy before they acquire the full capacity of unrestrained growth. Metastasis can develop from small cancers or even in the absence of detectable primary tumors (so-called''cancer of unknown primary,''). The reason could be that an early disseminated cell acquires an advantageous mutation at a distant site and evolves faster than the progenitor cell at the primary site.Those cells that evolved faster could build a fit microenvironment. The disseminated cells might be more likely to seeding into the site where cancer evolves faster. Tumor removal is followed by accelerated growth of locally recurrent tumors and metastases. The increase of disseminated cells seeding into the former less fit sites has been raised as a possible mechanism for the rapid expansion of locally recurrent tumors and metastases.The result of several clinical trials which testing inhibitors of matrix- metalloproteinases have been disappointing. Because that metastatic spread occurs early in progression,inhibitors of invasion should not be able to prevent it. Therapeutic attempts to better control cancer metastasis should therefore consider the interaction of primary and metastatic cancer.Cancer stem cells are more accurately called tumor-initiating cells. They could be the seeding cells that move between primary and metastatic site. The cancer stem cell model is not conflict with our model.In fact,we need more evident to support the authenticity of our hypothesis. With the aid of models for spontaneous metastasis and application of cell tracking technology,this hypothesis could be confirmed.