World-wide, men get more liver cancer than women. A hot new paper out of Michael Karin's lab provides new intriguing evidence that may help to explain why.
For several years, Karin's group has been interested in examining inflammation's role in hepatocellular carcinoma development. Now, their focus turns to estrogen-mediated suppression of the multifunctional cytokine IL-6 - a cytokine associated with systemic inflammation. Using IL-6-null mice, they demonstrate the requirement for IL-6 for development of hepatocellular carcinoma (HCC) in male mice.
DEN, a chemical carcinogen, damages murine hepatocytes and can cause the development of HCC in mice. While HCC incidence in DEN-treated wild-type males is 100% under this specific DEN administration protocol, the incidence in wild-type females is under 20%. However, HCC incidence in both IL-6-null males and females was less than 10%.
HCC is strongly associated with a background of chronic liver damage. IL-6 is thought to contribute to the stimulation of hepatocyte proliferation in response to liver damage and subsequent hepatocyte death. This study found profound differences in IL-6 expression in response to DEN between males and females.
The authors found that the administration of DEN resulted in higher levels of DEN-induced IL-6 production in male mice than in female mice. Furthermore, the administration of estrogen (E2) to male mice treated with DEN reduced DEN-induce IL-6 mRNA production and ovariectomy increased IL-6 mRNA levels in females. Using estrogen receptor alpha- and beta-null mice, they narrowed the E2-mediated suppression of IL-6 to estrogen receptor alpha.
IL-6 signals through STAT3, so it was not surprising that higher levels of activated STAT3 were detected in males than females after DEN treatment. Notably, growth hormone, also a prospective mediator of the sexual dimorphism of liver cancer, signals through STAT1, STAT3, and STAT5b - though STAT5b is considered to be the master regulator of sex-specific liver gene expression.
Estrogens are thought to decrease IL-6 expression by decreasing the activity of two transcription factors - nuclear factor kappa B (NF-kB) and C/EBP beta. Signaling through these factors involves IKK beta and Toll-like receptor (TLR) adaptor protein MyD88. MyD88-null male mice were found to develop fewer and smaller HCC tumors than wild-type males.
Due to these finding, the authors propose the use of estrogen-like compounds to prevent progression of HCC in men.
Naugler et al. 2007 [Science]
7.24.2007
7.08.2007
Castration a good thing? Yikes!
Androgen removal - castration - is an effective treatment for most human prostate cancers. The precise cellular and molecular mechanism of androgen removal-mediated regression is largely unknown.
Dividing cells require oxygen. Radiotherapy targets dividing cells. Therefore, especially hypoxic regions in a cancerous prostate tissue may harbor cancer cells that survive radiotherapy - resulting in recurrence.
A British study found that androgen removal increased the oxygen supply to prostate cancers - lessening hypoxia. This may partially explain the observed synergy of radiotherapy and androgen removal.
Milosevic et al. 2007 [Cancer research]
Dividing cells require oxygen. Radiotherapy targets dividing cells. Therefore, especially hypoxic regions in a cancerous prostate tissue may harbor cancer cells that survive radiotherapy - resulting in recurrence.
A British study found that androgen removal increased the oxygen supply to prostate cancers - lessening hypoxia. This may partially explain the observed synergy of radiotherapy and androgen removal.
Milosevic et al. 2007 [Cancer research]
College students average 16,000 words per day
College kids can't STFU.
A recent study published in Science found that both men and women average around 16,000 words per day (17 hours).
The authors claim women are generally considered to be more talkative than men - citing widespread media usage of a 7,000-versus-2,000 statistic used for the past 15 years. However, their study did not find significant sexual dimorphism. They conclude that "the widespread and highly publicized stereotype about female talkativeness is unfounded."
The study utilized the electronically activated recorder (EAR) to measure the number of words spoken per day in university students in 5 studies in the United States, 1 in Mexico. The students were recorded for as long as 10 days - as short as 2 days.
The EAR was modified to record 30 seconds of every 12.5 minutes. A sample word count was measured and used to extrapolate the number of words per day. And think - some poor graduate student that had to transcribe every recorded word.
Mehl et al 2007 [Science]
A recent study published in Science found that both men and women average around 16,000 words per day (17 hours).
The authors claim women are generally considered to be more talkative than men - citing widespread media usage of a 7,000-versus-2,000 statistic used for the past 15 years. However, their study did not find significant sexual dimorphism. They conclude that "the widespread and highly publicized stereotype about female talkativeness is unfounded."
The study utilized the electronically activated recorder (EAR) to measure the number of words spoken per day in university students in 5 studies in the United States, 1 in Mexico. The students were recorded for as long as 10 days - as short as 2 days.
The EAR was modified to record 30 seconds of every 12.5 minutes. A sample word count was measured and used to extrapolate the number of words per day. And think - some poor graduate student that had to transcribe every recorded word.
Mehl et al 2007 [Science]
Somatic Akt1 mutation found in human cancers
The Akt1 (v-akt murine thymoma viral oncogene homolog 1) pathway has long been associated with the activation of survival and proliferation pathways in cancer. However, Akt1 activation was thought to be mediated by somatic mutations in other pathway members (e.g. PI(3)K) - not mutations in Akt1.
This article describes an Akt1 mutation (Akt(E17K)) found in human breast, colorectal, and ovarian cancers. Rather than the catalytic domain, the mutation resides in a domain responsible for Akt1 membrane localization - the PHD (pleckstrin homology domain).
The Akt(E17K) mutation alters Akt1 subcellular localization - from the cytoplasm to the membrane - causing increased activation of Akt1. This mutation was able to transform rat fibroblasts and induced leukemia in mice.
Membrane localization of Akt1 drives Akt1 activation and subsequent downstream activation of oncogenic pathways. Anti-cancer drugs that target the PHD domain of Akt1 could be designed to block Akt1 activation.
Carpten et al. 2007 [Nature]
This article describes an Akt1 mutation (Akt(E17K)) found in human breast, colorectal, and ovarian cancers. Rather than the catalytic domain, the mutation resides in a domain responsible for Akt1 membrane localization - the PHD (pleckstrin homology domain).
The Akt(E17K) mutation alters Akt1 subcellular localization - from the cytoplasm to the membrane - causing increased activation of Akt1. This mutation was able to transform rat fibroblasts and induced leukemia in mice.
Membrane localization of Akt1 drives Akt1 activation and subsequent downstream activation of oncogenic pathways. Anti-cancer drugs that target the PHD domain of Akt1 could be designed to block Akt1 activation.
Carpten et al. 2007 [Nature]
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