Risky Business: Risk Assessment and Modeling

Centrosome amplification is a clear risk factor for tumor aggressiveness based on a wealth of research demonstrating its causative role in tumorigenesis and metastasis. The centrosome nucleates microtubules, organizes the mitotic spindle, spearheads directional cell migration and invasion, and serves as a hub of cell signaling. Normally, only one or two copies of this miniscule organelle are present in the cell depending on the cell cycle stage. In cancer cells, however, centrosomes are often amplified in number and/or volume, which amplifies microtubule nucleation and associated activities, such as migration and invasion. When greater than two centrosomes are present in a cell, a transient multipolar state occurs during prophase that predisposes microtubules to form erroneous merotelic attachments to kinetochores. Cancer cells then cleverly resolve this multipolar state by clustering supernumerary centrosomes into two groups so that a pseudobipolar spindle can be constructed. However, due to persistently uncorrected merotelic attachments, some chromosome missegregation occurs during anaphase. As a result, centrosome amplification causes chromosomal instability, which empowers cancer cells to evolve when faced with adverse environmental conditions, such as nutrient scarcity, chemotherapy and radiation, or immune surveillance, breeding intratumor heterogeneity and ever-more aggressive subclones.

Given that centrosome amplification drives tumor evolution of more aggressive traits, we strongly believe that this “risk contributor” should be included in models of cancer risk, prognosis, and treatment response. Currently risk models completely overlook such organellar disturbances. We are characterizing and quantitating centrosome amplification in detail in cell lines and clinical specimens and incorporating these data into computer models that would allow identification of high-risk individuals whose disease needs to be treated more aggressively; low-risk individuals on the other hand may be treated with less harsh regimens. Incorporation of centrosomal profiles into prognostic and predictive models represents a revolutionary concept in cancer research.