A Fork in the Road: The Effects of Different Cellular Pathways on Melanoma
Ras is commonly mutated in malignant melanoma. This simplified schematic summarizes the observed outcomes of activation of three prominent Ras downstream pathways in melanin-producing primary cells. Raf and PI3K seem to play important roles in senescence and invasiveness, respectively. Notably, Ral activation has a major impact on several malignant phenotypes, particularly anchorage-independent growth.
Malignant melanoma is one of the most deadly forms of cancer because of its high capacity to metastasize and because there are few treatments effective in stopping its progression. The extensive body of research on melanoma has identified several important protein mutations that contribute to development of the disease. One of these proteins, Ras, is mutated in 25 percent of cutaneous malignant melanomas. These mutations disrupt Ras regulation, switching the protein permanently "on," leading to constant signaling of cellular messengers and stimulating growth without normal checks and balances.
Ras interaction with a variety of proteins sends messages through different signaling pathways to control cellular functions. Prasun J. Mishra, Ph.D., Linan Ha, Ph.D. and Jennifer Rieker, M.S. of the CCR Laboratory of Cancer Biology and Genetics, study Ras to better understand how abnormal cell signaling leads to melanoma. A report of the consequences of altered Ras downstream signaling by Mishra, Ha, Rieker and their colleagues was recently published in Oncogene.
The researchers employed melanin-producing primary mouse cells grown in culture to look at the effects of the activation of three different Ras downstream signaling proteins individually or in combination. The effects were then compared with cells producing oncogenic Ras. The three proteins, Ral, Raf, and PI3K have been previously implicated in formation of melanomas, but the specific effect of each pathway is unknown.
One hallmark of cancerous cells is their ability to grow without the normal cellular requirement of attachment to a support. Cells producing a mutated Ral-activating protein alone or the combination of mutants of PI3K and the Ral activator were able to grow in the absence of support similar to cells with a Ras mutation. However, expression of mutants of Raf and PI3K alone or together were unable to overcome this requirement.
Metastasis of tumors cells requires that they move through other tissues to reside in sites throughout the body. When cells produce mutated Ras, they acquire this ability to penetrate other tissues. Activation of Ral and PI3K by mutation allowed for a similar gain in invasiveness, while cells with activated Raf did not.
Since the activation of Ral leads to changes characteristic of cancerous cells, the researchers next determined whether inhibiting Ral could prevent Ras-mediated transformation. Cells expressing activated Ras and an inhibitory form of Ral lost the ability to grow without cellular support and behaved more similarly to normal cells.
The research performed by Mishra, Ha, Rieker and colleagues demonstrates that the ability of Ras to transform skin cells is dependent upon its activation of a collection of diverse signaling pathways. A prominent role for Raf, PI3K and Ral in melanocyte senescence, invasiveness and transformation, respectively, is suggested. This study also identified a new role for Ral signaling in contact-independent growth. The discovery of a new player in melanoma expands the number of potential drug targets and could lead to better melanoma treatments.Summary Posted: 02/2010
Oncogene. 2010 Feb 1. [Epub ahead of print] PubMed Link