Results of the self-study : a simple, but testable hypothesis…

Novel approaches to identify target genes for metastasis and pre-metastatic niche, within the context of cancer stem-cell niche /microenvironment

Physician Stephen Paget's 1889 proposal still holds forth today that metastasis is a multistage process that requires intravasated cancer cells to escape from the primary tumors (the ‘seeds’), survive in the circulation, arrive at the target or specific organ microenvironments and grow (the ‘soil’). Each of these stages is inefficient and some of them are rate-limiting steps that are supported by the functions of the cancer cells themselves, the tumor stroma the tumor microenvironment. Recently, a number of reports have highlighted that the embryonic microenvironment clearly suppresses the malignancy of potentially metastatic cells (ref.) nevertheless, the steps to re-activation that forms a clinically relevant metastasis probably occur through perturbations in the microenvironment.

A great deal of evidence increasingly supports the role of the tumor microenvironment in the development of cancer metastasis, but there currently is no proof of a correlation at the level of the role of cell surface microenvironments in the modulation of receptor signaling. This is probably due to the very complex nature of cancer microenvironments. In order to translate the basic research and help to augment the number of cancer survivors, we would, therefore, like to suggest the following solution in order to identify novel target genes:

First step: list the genes that are initiating the tumor functions; such as oncogenes (EGFR, ERBB2, cMYC, CTNNB1 (beta-catenin), KRAS, PI3K), tumor suppressors (APC, BRCA1, BRAC2, TP53, and PTEN);Second step: list the genes that are causing the metastatic functions (gain of functions such as ID1, MET, SNAI, SNAI2, as well as loss of functions such as DARC, GPR56, KISS1);The third step: list the genes that are responsible for metastatic progression; such as ANGPTL4, CCL5, EREG, LOX, MMP1, and PTGS2;The final step is to list the genes that cause the metastatic virulence functions such as IL6, IL11, and CSF2RB (GM-CSF), PTHRP, TNF-alpha.

After the above listings and/or the preparative steps, we will begin to modulate the genes and their signaling pathways (EGFR, for example) in each step and study their effects on the cell surface microenvironment. Since the cancer stem-cell niche/microenvironment plays a fundamental and important role in spreading the cancer cells, we hope that beginning with a basic approach will not only give us opportunities to identify novel target genes which could define the interactions between the cancer cells and the microenvironment, but may also, due to the altered properties of cancer stem-cell niches/microenvironments, create opportunities to study how these genes and their signaling pathways contribute to metastasis, pre-metastatic niche, etc. Furthermore, since abnormal cell signaling pathways are a hallmark of cancer cells, discovering how they interact with each other could also offer further important clues as to how to halt tumor cell division, survival, or metastasis.