The line between cell survival and cell proliferation in cancer
Tumor cells are fundamentally different than normal, healthy cells. In tumors, the clockwork genetic mechanisms that control the life cycle of cells are entirely disrupted, a fact that may hold the key to defeating cancer. The Altieri laboratory is interested in how tumor cells evade apoptosis – also known as programmed cell death – which is the process that normally causes dysfunctional cells to self-destruct. Bypassing apoptosis is a hallmark of cancer, and medical science is eager to find new ways of “reprogramming” cancer cells to die.
The Altieri laboratory studies a family of genes, known as Inhibitors of Apoptosis (IAP), that are essential for the cell life cycle to run smoothly. In normal cells, the proteins these genes produce are thought to prevent apoptosis during normal cell division and the direct inhibition of caspases – the enzymes chiefly responsible for promoting apoptosis – in cells. In particular, Altieri has demonstrated that at least one IAP gene, called survivin, retains the ability to participate in both functions, and has been shown to be over-produced in virtually every human cancer.
Altieri and his team are currently focused on three programs to understand the biology of survivin and how exploiting this biology may provide new cancer therapies:
1) The role of survivin in cell division
2) The ability of survivin to inhibit apoptosis
3) The link between cell division and apoptosis
The role of survivin in cell division
Cells produce – or “express” – great quantities of survivin just before they undergo the process of cell division, also called mitosis. Upon expression in dividing cells, survivin is rapidly recruited to various aspects of the mitotic apparatus, the scaffolding of microtubules that serve to physically separate and sort the proper complement of chromosomes into each of the two new cells that result from mitosis. The Altieri laboratory has extensively used cell biological approaches to probe the function of survivin at cell division. For instance, the laboratory has unraveled multiple roles of survivin at cell division, all of which ensure that the physical act of cell division occurs properly.
The ability of survivin to inhibit apoptosis
In addition to a critical role in cell division, it is also clear that survivin has a function in protecting cells from apoptosis and that this pathway is followed in nearly every human tumor. Altieri and his colleagues have used biochemical and genetic approaches to study the role of survivin in apoptosis inhibition. They have found that animals engineered to express survivin in the skin exhibit strong resistance to apoptosis induced by ultraviolet B irradiation and that these animals are more prone to develop aggressive skin cancers. Conversely, they have found that interfering with survivin expression in tumor cells is sufficient to trigger apoptosis, to enhance the efficacy of conventional anti-tumor treatment, and to exert potent anti-tumor activity in vivo.
The link between cell division and apoptosis
A third line of investigation in the Altieri laboratory focuses on the potential role of survivin as a determining factor between cell division and cell death through apoptosis. Using biochemical and cell biological approaches, they have identified a critical event in survivin function that links the two properties of the protein. During cell division, a protein, known as Cdk1, alters a single amino acid component of the survivin protein. This acts to stabilize survivin during mitosis, and when the researchers prevent this from happening, it results in the beginning stages of apoptosis, activation of the caspase enzymes, which further promote apoptosis, and strong anti-cancer activity, in various animal models of cancer.