Gene expression profiling with microarrays has shown promise in prognosis by identifying patterns of expression that are correlated with metastasis. However, these patterns of expression do not reveal clues as to mechanisms of invasion and metastasis and can appear as random sets of genes with unrelated functions. We have performed expression profiling of invasive carcinoma cells, which are caught in the act of invading inside tumors, to reveal gene expression patterns that are specific to invasive cells. Our analysis indicates that invasion genes are grouped into pathways of functionality and give insight into their mechanism. The patterns of gene expression of invasive cells are usually not seen in their entirety in expression profiles derived from whole tumors suggesting that invasion, and the patterns of gene expression that support it, are transitory. This leads to a new model of invasion called the tumor microenvironment invasion model (TMIM) where tumor progression leads to the development of microenvironments encoded within the tumor which elicit the transient gene expression patterns that support invasion. TMIM is a very different view of the events leading to metastasis compared to the conventional model. In the conventional model, the process of progression of the tumors from early carcinoma to metastatic carcinoma is compared to Darwinian evolution in which favorable mutations are accumulated in rare cells during tumor progression. The conventional model does not fit current evidence from profiling studies. However, TMIM is consistent with these findings, in particular that genes encoding the tumor microenvironment for invasion and metastasis can be encoded throughout the bulk of the tumor and that they may not be related as pathways of functionality. An experimental plan was designed to investigate the transitory nature of the patterns of gene expression unique to invasive cells. The invasive tumor cells were collected by chemotaxis and removed from the microenvironment. These cells were then grown in cell culture environment for 12-168 hrs. QRT-PCR was performed on these cells to look for the expression of genes that regulate motility. The resident tumor cells were used as controls for the experiment.It was observed that the gene expression patterns exhibited three different patterns of stability. Some of the genes were stably expressed over seven days in culture, indicating a stable genetic change in the invasive cells. There were two groups of genes whose expression returned to the levels of non-invasive cells during the culture period either within 36 hrs in culture or within 72 hrs in culture. We are currently studying the molecular mechanism of these stable and transient changes in the gene expression pattern of the invasive cells.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]