Cellular senescence and cancer treatment

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Cellular senescence and cancer treatment

Source:

Biochimica et Biophysica Acta (BBA) – Reviews on Cancer. Volume 1775, Issue 1, January 2007, Pages 5–20

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Fig. 1. Features of cellular senescence. (A) Schematic view of a senescent cell population with characteristic morphological alterations and typical biochemical markers, including the elevated activity of β-galactosidase at an acidic pH and numerous secreted, cytoplasmic or nuclear proteins found expressed at increased levels or with a distinct pattern (e.g. heterochromatinization) in the senescent condition. (B) Drug-induced senescence-associated β-galactosidase activity visualized in a cytospin preparation of murine, Ras-driven T-cell lymphoma cells 5 days after exposure to 0.1 μg/ml adriamycin.

 

Cellular Senescence 

Cellular senescence, an irreversible cell-cycle arrest, reflects a safeguard program that limits the proliferative capacity of the cell exposed to endogenous or exogenous stress signals. A number of recent studies have clarified that an acutely inducible form of cellular senescence may act in response to oncogenic activation as a natural barrier to interrupt tumorigenesis at a premalignant level. Paralleling the increasing insights into premature senescence as a tumor suppressor mechanism, a growing line of evidence identifies cellular senescence as a critical effector program in response to DNA damaging chemotherapeutic agents. This review discusses molecular pathways to stress-induced senescence, the interference of a terminal arrest condition with clinical outcome, and the critical overlap between premature senescence and apoptosis as both tumor suppressive and drug-responsive cellular programs.

More than 40 years ago, Hayflick and Moorhead described the observation of growth arrested human diploid cells that apparently exhausted their capacity to divide in vitro as “replicative senescence”, assuming a central role of this phenomenon in cellular and possibly organismic aging. Decades later, DNA damage signals emanating from eroded telomeres that progressively shorten every time the cell divides were unveiled as the underlying mechanism of the irreversible block in the G1-phase of the cell-cycle. Over the past several years, acutely stress-responsive forms of cellular senescence have been discovered that seem to play important roles in tumor development and treatment responses. Of note, other, not necessarily G1-restricted senescence-like forms of lasting cell-cycle blocks certainly do exist, and may reflect either a programmatic variation or an adapted response when signaling components determined to execute a “classic” G1-senescent arrest are no longer available. Based on the advanced biological characterization and the increasing mechanistic understanding, this review will mostly focus on cellular senescence that occurs in late G1 in the context of the retinoblastoma (Rb) protein restriction point.

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Fig. 4. Oncogenic provocation of failsafe responses, their mutational inactivation or regulatory suppression as the basis for malignant transformation, and the subsequent availability of these programs as drug-inducible effector mechanisms.

The understanding and utilization of cellular senescence in cancer therapy has become an emerging field of extensive research. Standard chemotherapeutic regimens are now recognized to exert their therapeutic potential not only via forcing cancer cells to die but by promoting a terminal arrest program that contributes to the outcome of cancer therapy as well. Future analyses will address whether drug-inducible senescence might even act as the essential therapeutic component in determining tumor control versus relapse particularly at the level of minimal residual disease. Importantly, little is known about the ultimate fate of senescent tumor cells in situ, and, vice versa, the immediate and long-term impact treatment-induced senescent cancer cells may have on their local environment.

At least under certain experimental conditions, acutely inducible senescence has been shown to be a formally reversible program thereby raising concerns about its lasting therapeutic impact. However, it remains to be demonstrated that a resting tumor cell in its natural environment is indeed capable of acquiring critical genetic defects in the absence of DNA synthesis. Moreover, attempts to experimentally reverse senescence entirely focus on a forced cell-cycle re-entry, often regardless of proper subsequent cell divisions, and, so far, have neglected the possibility that the regulatory chromatin-involving principles underlying cellular senescence might produce a reprogrammed phenotype that goes well beyond a terminal cell-cycle block.

The evidence that therapeutic strategies can be employed to force fully transformed cancer cells to (re-)enter the senescence program on the one side and the rapidly growing data on novel regulators of cellular senescence on the other side fuel the exciting perspective that targeted utilization of the senescence machinery may become a therapeutic option in the near future.

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