. Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer's disease. J Neurosci. 2010 Aug 25;30(34):11251-8. PubMed.

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  1. This is a fascinating study. I think the authors have made a convincing case that AD mice develop fewer, and smaller, gliomas compared to their wild-type littermates. Further, there was much less vascularization surrounding the tumors in the AD mice, suggesting that the slowed tumor growth was due to decreased angiogenesis in these mice. This was demonstrated using two strains of mice, which I believe lends further confidence in the results.

    I would be interested to see whether these results extend to solid tumors at other body sites. There is some preliminary epidemiological evidence that the development of cancer and AD may be inversely associated in humans, although there is much work to be done before concluding that such a relationship does indeed exist. A limitation of the work of our group in this area is that we were unable to examine associations between AD and cancer development by cancer type, given the low frequency of individual site-specific cancers. Therefore, we can only conclude that AD may be inversely associated with multiple cancer types. However, an amyloid-β-related mechanism that affects tumor growth and vascularization, as suggested by the results of Paris et al., would provide an explanation for an inverse relationship between AD and solid-tumor cancers at many sites.

    Interestingly, we also know that people with Down syndrome, who develop amyloid-β plaques at a young age, have a lower incidence of solid-tumor development compared to individuals without Down syndrome. Some research suggests that this may be due to decreased angiogenesis (Reynolds et al., 2010). In any case, Paris et al. are carrying out an exciting line of research, and I look forward to their next report.

    References:

    . Tumour angiogenesis is reduced in the Tc1 mouse model of Down's syndrome. Nature. 2010 Jun 10;465(7299) PubMed.

  2. In this paper, researchers report that GL261 murine glioma cells were implanted in the brains of six-month-old Tg APPswe, Tg PS1/APPswe, and wild-type littermate mice which were sacrificed after three weeks. At that age, Tg APPswe mice have elevated brain levels of Aβ but do not yet have Aβ plaques, in contrast to Tg PS1/APPswe mice, which have higher levels of Aβ and already develop Aβ plaques. Since both APP Tg mouse models also express full-length APP and other APP metabolites, it is not clear if Aβ is responsible for tumor growth inhibition. A good control would have been to compare the APPswe and Tg PS1/APPswe mice with a model overexpressing wild-type APP. It is puzzling that there is no dose-dependent effect of Aβ, the levels being higher in TgPS1/APPswe. Therefore, it would be very interesting to investigate if a loss of the trophic APP function (controlled by secreted APPα) is responsible for the effect in vivo.

    Maria Isabel Behrens, Corinne Lendon, John Morris, and Cathy Roe have previously pointed out a very interesting inverse relation between Alzheimer’s and cancer. They have demonstrated that “the presence of one disease was found to correlate with a reduced probability of subsequently diagnosing the other. This association was observed for dementia of the Alzheimer’s type, but not for vascular dementia, suggesting the existence of a common biological mechanism underlying neurodegenerative disorders and cancer” (1-3).

    We have recently found evidence supporting these findings (4). APP has an important function in the pathogenesis of pancreatic and colon cancer cell growth. A growing number of reports revealed full-length APP as a potential tumor marker, especially in prostate, pancreatic, melanoma, and oral squamous cell carcinoma. More than that, the rate of cancer-specific survival for patients with APP-positive tumors was significantly lower than those with APP-negative tumors. These studies are in good agreement with our findings that APP and secreted sAPPα are tightly involved in cancer development (5-8).

    We found that valproic acid, a histone deacetylase (HDAC) inhibitor downregulating APP and sAPPα in colon and pancreatic tumor cells, increased expression of GRP78 (an ER chaperone), known to bind APP. Thereby, APP maturation and transport was blocked, which is a prerequisite to generate sAPPα at the plasma membrane. Moreover, APP was found to be overexpressed only in malignant cells of tumor tissue from patients (4). Therefore, we strongly believe that the secreted form of APP (sAPP) has a dominant role in tumor growth activity.

    Serrano et al. used a different approach to study the connection between cancer and Alzheimer’s. They injected the carcinogen 20-methylcholanthrene in the brain of APPswe/PS1-A246E mice (9). Transgenic mice developed tumors faster and with higher incidence than their wild-type littermates. This finding is seemingly contradictory to the data by Paris et al. However, we believe that in both approaches the growth-promoting effect of APP cannot be ruled out in addition to a possible toxic function of Aβ.

    In addition, the suggested molecular mechanism for how Aβ could inhibit neo-angiogenesis and tumor growth needs further investigation.

    References:

    . Alzheimer disease and cancer. Neurology. 2005 Mar 8;64(5):895-8. PubMed.

    . Cancer linked to Alzheimer disease but not vascular dementia. Neurology. 2010 Jan 12;74(2):106-12. PubMed.

    . A common biological mechanism in cancer and Alzheimer's disease?. Curr Alzheimer Res. 2009 Jun;6(3):196-204. PubMed.

    . Histone deacetylase inhibitor valproic acid inhibits cancer cell proliferation via down-regulation of the alzheimer amyloid precursor protein. J Biol Chem. 2010 Apr 2;285(14):10678-89. PubMed.

    . Increased expression and processing of the Alzheimer amyloid precursor protein in pancreatic cancer may influence cellular proliferation. Cancer Res. 2003 Nov 1;63(21):7032-7. PubMed.

    . Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth. Cancer Res. 2009 Jan 1;69(1):137-42. PubMed.

    . Increased expression of amyloid precursor protein in oral squamous cell carcinoma. Int J Cancer. 2004 Sep 20;111(5):727-32. PubMed.

    . Induction of terminal differentiation in melanoma cells on downregulation of beta-amyloid precursor protein. J Invest Dermatol. 2010 May;130(5):1400-10. PubMed.

    . High sensitivity to carcinogens in the brain of a mouse model of Alzheimer's disease. Oncogene. 2010 Apr 15;29(15):2165-71. PubMed.

  3. The Alzheimer's Disease and Cancer Relationship
    These results raise the question of whether amyloid-β peptides might be useful anti-cancer agents. It also adds further support to the idea that amyloid-β has differential effects on pluripotent/totipotent (e.g., Porayette et al., 2009) and differentiated (e.g., Liu et al., 2004) cell types.

    References:

    . Differential processing of amyloid-beta precursor protein directs human embryonic stem cell proliferation and differentiation into neuronal precursor cells. J Biol Chem. 2009 Aug 28;284(35):23806-17. PubMed.

    . Amyloid-beta-induced toxicity of primary neurons is dependent upon differentiation-associated increases in tau and cyclin-dependent kinase 5 expression. J Neurochem. 2004 Feb;88(3):554-63. PubMed.