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  current news   Press   selected story    
     
  20th May 2009  
 

Inflammation and cancer: the plot gets thicker

 
 




Abstract
The past few years have provided fresh evidence for the notion that inflammation is as critical a component of tumour initiation and progression as the 6 other components (called “hallmarks of cancer”) highlighted by Weinberg and Hanahan (Cell, 2000; 100(1):57-70). Up to 30% of human cancers arise at sites of infection, chronic irritation or inflammation (EBV, HPV, Helicobacter driven cancers to name a few). It is now evident that inflammatory cells in the tumour microenvironment make, and help other cells make, “goodies” (cytokines, chemokines, growth factors, receptors for invasion and migration) that are indispensable for the 6 major components (which include proliferation, growth factor independence, resistance to apoptosis, angiogenesis and invasion/metastasis) to work. The cross talk between tumour suppressor pathways, such as those controlled by the p53 network and inflammatory pathways controlled by NFκB, are a topic of research in Vinay Tergaonkar’s NFκB signalling laboratory in IMCB1,2,3,4. Two studies published recently from this laboratory have uncovered new links between inflammatory pathways and tumour suppressor pathways. In a study published in a February issue of PNAS, the authors show that IKK2, the key kinase that drives inflammation, also orders the destruction of the tumour suppressor protein p53 by marking it for ubiquitination and subsequent proteosomal degradation5. These results, obtained in collaboration with scientists from the Salk Institute, USA, provide a fresh mechanism by which cells in the tumour microenvironment with sustained inflammation (hence high IKK2 activity) become more susceptible to tumour development (since p53 function is compromised).

In another study published in the recent issue of Nature Cell Biology, Vinay Tergaonkar’s group, working in close collaboration with Dmitry Bulavin’s lab, also at IMCB, reports that a phosphatase that has been known to regulate p53 can also negatively regulate NFκB6. Since WIP1 has been proposed to be oncogenic, its ability to negatively regulate NFκB and inflammation is counterintuitive in the context of cancers and needs further investigation. Given that too much NFκB activation is also not good for cells, WIP1 might be required to keep levels of constitutive NFκB activity under control in cancers. Furthermore, the authors also show that WIP1-mediated negative regulation of inflammation is critical in the context of another serious medical condition called sepsis6. Caused by infection, sepsis is characterized by a whole-body inflammatory state (called as systemic inflammatory response syndrome or SIRS), and it is a major cause of death in intensive care units worldwide, the leading cause of death in non-coronary ICU patients, and the tenth-most common cause of death in United States. These insights are fostering new anti-inflammatory therapeutic approaches to human ailments ranging from inflammation to cancer7,8. Sathyavageeswaran Shreeram from Dmitry Bulavin’s lab, Cheok Chit Fang from David Lane’s Lab and Joanne Chew, Mahathir Humaidi, EeTsin Wong, Hsiangling Teo and Amit Hazra from Vinay Tergaonkar’s lab contributed to the WIP1 study. The work from Vinay Tergaonkar’s laboratory is supported by collaborations with other laboratories, including those of Tony Hunter, Inder Verma, David Lane, Shizuo Akira, and Dmitry Bulavin.

1) Ghosh S, Tergaonkar V*, Rothlin CV, Correa RG, Bottero V, Bist P, Verma IM, Hunter T. Cancer Cell. 10(3):215. 2006

2) Tergaonkar V*, Perkins ND. Molecular Cell. 26(2):158. 2007

3) Biswas SK, Bist P, Dhillon MK, Kajiji T, Del Fresno C, Yamamoto M, Lopez-Collazo E, Akira S, Tergaonkar V*. Journal of Immunology. 179(6):4083. 2007

4) Dey A, Wong ET, Cheok CF, Tergaonkar V*, Lane DP. Cell Death Differ. (2):263. 2008

5) Xia Y, Padre RC, De Mendoza TH, Bottero V, Tergaonkar VB*, Verma IM. PNAS. 106(8):2629. 2009

6) Joanne Chew, Subhra Biswas, Sathyavageeswaran Shreeram, Mahathir Humaidi , Ee Tsin Wong, Manprit Kaur Dhillion, Hsiangling Teo, Amit Hazra, Cheok Chit Fang Eduardo López-Collazo, Dmitry V. Bulavin & Vinay Tergaonkar*. Nature Cell Biology. 11(5). 2009

7) Dey A, Tergaonkar V*, Lane DP. Nature Reviews Drug Discovery. 7(12):1031. 2008

8) Sethi G, and Tergaonkar V*. Trends in Pharmacological Sciences. In Press. 2009

* Co/Corresponding Author  

 
 


 
 


For more information on Vinay TERGAONKAR’s Lab, Please Click here.