Escaping growth arrest in cancer

Abstract

We now have a general idea of which genes and cellular pathways are central in cancer development: uncontrolled growth governs establishment and spread of the disease. Nevertheless, to fully appreciate the consequences of the interplay of driver mutations in this genetic disease it is imperative we understand the mechanisms behind uncontrolled growth, or escape of growth arrest, in cancer. It is still not fully understood how cells escape the tumor-suppressing activity of p53, the most mutated gene in cancer. How p53 is regulated and recruited to protect against tumor formation is well known, but it is less well known how it executes this function. By studying the tumor-suppressive activity of p53 in both a biased and unbiased manner I have identified various molecules and mechanisms that may intersect with p53 function when it comes to uncontrolled cell growth, or tumor initiation. I have found that there is a reciprocal regulation of p53 and growth stimulatory signals, since activation of p53 results in an arrest in the cell cycle, or senescence, by blocking growth signaling, and that hyperactive growth factor signaling can override p53 function. Interestingly, plasminogen activator inhibitor-1 (PAI-1), one of the molecules I found to be causally involved in senescence, and which normally is activated by p53 under stressful conditions, is a secreted protein and has its most direct function on the outside of a cell. Hence, it can be regarded a gatekeeper of cell cycle progression. My findings also suggest that a molecule that formerly was coupled to extra-cellular cross-talk between cells and wound-healing apparently directly controls cycling of a cell. PAI-1 was already known to be involved in tumor progression (a process dependent on excessive communication between cells), since it highly influences metastatic behavior of a cell. For example, quantification of this molecule is used in the clinic as a marker for breast cancer progression. Next to this I screened for genes that, when hyperactivated, interfere with anti-tumorigenic p53 activity, and found that lysophosphatidic acid (LPA) activity induce a senescence-bypass. LPA is a lipid involved in growth and wound healing processes. This further supports the notion that growth factor- and p53 signaling are linked. I also found that TGFbeta, a molecule with strong tumor suppressive activity, needs PAI-1 for its anti-tumorigenic effect. One of the biggest questions regarding TGFbeta dependent tumorigenesis is what mutations drive the transition from tumor intitiation to tumor progression or, in other words, what mutations make cells less sensitive to innate anti-tumorigenic activity of stress signals. I hypothesize that PAI-1 may be a central player and necessary downstream of both anti-tumorigenic p53- and TGFbeta signaling. My findings shed light on how intra-cellular tumor-suppressive gene programs result in specific communicative behavior of cells, and support the notion that wound healing and tumor-progression have parallel mechanisms. Furthermore, it provides us insight in the cross-talk between some of the key players in cancer initiation and progression which were previously not linked.