Cancers, including colon, prostate, and leukemia, continue to grow unchecked

Sep 8 2004

Many cancers, including colon, prostate, and leukemia, continue to grow unchecked because they do not respond to a signal to die and stop proliferating from Transforming Growth Factor-beta (TGF-b).

The cause of this signaling disruption of the normal cell cycle has not been fully understood. For the first time, scientists at Memorial Sloan-Kettering Cancer Center have discovered the biologic function of the cytoplasmic form of the Promyelocytic Leukemia protein (PML), and identified it as an essential factor in maintaining TGF-b signaling. Their findings, published in the September 9 issue of the journal Nature, explain the link between these two proteins in the development of cancer and suggest that restoring their activity may provide a possible cancer treatment.

"Through our discovery of the biologic function of PML and its essential role in maintaining TGF-b signaling, we can better understand the progression of many human cancers," said Pier Paolo Pandolfi, M.D., Ph.D., Head of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering and the study's senior author. "Restoring PML function may correct this signaling defect therefore providing a novel therapeutic target for cancer drugs."

TGF-b is a protein that can suppress tumor development by signaling a cell to stop growing. The unresponsiveness to TGF-b signaling has been associated with a variety of human cancers. In addition to this loss of TGF-b, loss of PML is associated with tumor progression in many human cancers, including prostate, breast, colon, and lung, as shown by Dr. Pandolfi and colleagues in a recently published study in the Journal of the National Cancer Institute. In a later work published in Nature Cell Biology, they also demonstrated an unexpected role for PML in affecting the nucleolar network for tumor suppression and in regulating the function of a gene crucial to the suppression of the genesis of cancer.

In this current work, the Sloan-Kettering researchers found that cytoplasmic PML (cPML) also has a key role in cancer development. It is required for the formation of a signaling complex that is an essential factor in activating TGF-b signaling necessary to suppress the growth of cancer cells. When cPML is lost, TGF-b signaling is disrupted. Primary cells from Pml-null mice are resistant to TGF-b dependent growth arrest, induction of aging (cellular senescence), and cell death (apoptosis). However, when PML function is added back to these cells, this defect is corrected and TGF-induced activity restores normal cell functions.

"The study found an unexpected role of cPML which highlights the importance of analyzing the status of PML in human cancers," said Hui-Kuan Lin, Ph.D., of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering and the study's first author.