The following paper is from a friend of mine in Yale. His mentor just gave a seminar about it at the end of last year. In the paper, they present evidences that oncogenic mutations do NOT have to be in the same cells to drive cancer development. Instead, distinctive mutations occurring in neighboring cells could cooperate to drive tumor formation.
It is a very interesting paper. Hit-Two definitely has higher chances than Two-Hit. In the end of the paper, they even show that wounding elevated JNK signaling could cooperate with RasV12 to promote tumorigenesis.
It is definitely a new angel to battle with cancer. However, if this mechanism is generally true, shouldn’t we anticipate a lot more cancer incidences? I don’t know the age of the flies used in these experiments. Is it possible that aging process switches the tumorigenesis mechanism from Two-Hit to Hit-Two?
News from HHMI: “Mutations in Different Cells Cooperate to Set the Stage for Cancer”
Nature advance online publication 13 January 2010
DOI: 10.1038/nature08702Interaction between RasV12 and scribbled clones induces tumour growth and invasion
Ming Wu 1,3, José Carlos Pastor-Pareja 1,3 & Tian Xu 1,2
1 Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, 295 Congress Avenue, New Haven, Connecticut 06519, USA
2 Fudan-Yale Biomedical Research Center, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, 220 Han Dan Road, Shanghai 20043, China
3 These authors contributed equally to this work.Correspondence to: Tian Xu 1,2 Correspondence and requests for materials should be addressed to T.X. (Email: tian.xu@yale.edu).
Human tumours have a large degree of cellular and genetic heterogeneity1. Complex cell interactions in the tumour and its microenvironment are thought to have an important role in tumorigenesis and cancer progression2. Furthermore, cooperation between oncogenic genetic lesions is required for tumour development3; however, it is not known how cell interactions contribute to oncogenic cooperation. The genetic techniques available in the fruitfly Drosophila melanogaster allow analysis of the behaviour of cells with distinct mutations4, making this the ideal model organism with which to study cell interactions and oncogenic cooperation. In Drosophila eye-antennal discs, cooperation between the oncogenic protein RasV12 (ref. 5) and loss-of-function mutations in the conserved tumour suppressor scribbled (scrib)6, 7 gives rise to metastatic tumours that display many characteristics observed in human cancers8, 9, 10, 11. Here we show that clones of cells bearing different mutations can cooperate to promote tumour growth and invasion in Drosophila. We found that the RasV12 and scrib- mutations can also cause tumours when they affect different adjacent epithelial cells. We show that this interaction between RasV12 and scrib- clones involves JNK signalling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines, a compensatory growth mechanism for tissue homeostasis. The development of RasV12 tumours can also be triggered by tissue damage, a stress condition that activates JNK signalling. Given the conservation of the pathways examined here, similar cooperative mechanisms could have a role in the development of human cancers.
* the power of fly genetics …
One Response to “Hit-Two vs Two-Hit: cooperation between different cancer-causing mutations promote tumorigenesis”
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New in 'Theory'
Norbert Perrimon
Harvard Medical School & Howard Hughes Medical Instutite, United States of America
Developmental Biology
This study documents the surprising finding that, in Drosophila, different mutations occurring in adjacent neighboring epithelial cells can cooperate to promote tumorigenesis.
Previous work from Tian Xu’s lab had shown that, while epithelial cells that express RavV12, an oncogenic form of the Ras85D protein, overgrow moderately, these cells when missing apico-basal polarity, as is the case in the absence of the Scribble protein, grow into large metastatic tumors. In this paper, Wu et al. show that these two events do not need to occur in the same cell, as mutations in RasV12 and scribble can cooperate and cause tumors when present in adjacent cells. Further, they show that this process is mediated by activation of the JAK/STAT kinase pathway that is induced as a result of activation of the kinase JNK in cells that lack Scribble activity. These studies underscore the importance of “context” in the development of human cancers.
http://f1000biology.com/article/id/1556034/evaluation