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High tumour cannabinoid CB(1) receptor immunoreactivity negatively impacts disease-specific survival in stage II microsatellite stable colorectal cancer
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences.ORCID iD: 0000-0002-9933-2843
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
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2011 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 6, no 8, 1-11 p.Article in journal (Refereed) Published
Abstract [en]

Background: There is good evidence in the literature that the cannabinoid system is disturbed in colorectal cancer. In the present study, we have investigated whether CB(1) receptor immunoreactive intensity (CB(1)IR intensity) is associated with disease severity and outcome.

Methodology/Principal Findings: CB(1)IR was assessed in formalin-fixed, paraffin-embedded specimens collected with a consecutive intent during primary tumour surgical resection from a series of cases diagnosed with colorectal cancer. Tumour centre (n = 483) and invasive front (n = 486) CB(1)IR was scored from 0 (absent) to 3 (intense staining) and the data was analysed as a median split i.e. CB(1)IR <2 and >= 2. In microsatellite stable, but not microsatellite instable tumours (as adjudged on the basis of immunohistochemical determination of four mismatch repair proteins), there was a significant positive association of the tumour grade with the CB1IR intensity. The difference between the microsatellite stable and instable tumours for this association of CB(1)IR was related to the CpG island methylation status of the cases. Cox proportional hazards regression analyses indicated a significant contribution of CB(1)IR to disease-specific survival in the microsatellite stable tumours when adjusting for tumour stage. For the cases with stage II microsatellite stable tumours, there was a significant effect of both tumour centre and front CB(1)IR upon disease specific survival. The 5 year probabilities of event-free survival were: 8565 and 66+/-8%; tumour interior, 86+/-4% and 63+/-8% for the CB(1)IR<2 and CB(1)IR >= 2 groups, respectively.

Conclusions/Significance: The level of CB(1) receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB(1)IR is indicative of a poorer prognosis in stage II microsatellite stable tumour patients.

Place, publisher, year, edition, pages
San Francisco, CA: Public Library of Science , 2011. Vol. 6, no 8, 1-11 p.
National Category
Biomedical Laboratory Science/Technology Biological Sciences
URN: urn:nbn:se:umu:diva-47396DOI: 10.1371/journal.pone.0023003OAI: diva2:443032
Available from: 2011-09-23 Created: 2011-09-20 Last updated: 2015-03-24Bibliographically approved
In thesis
1. Cannabinoids as modulators of cancer cell viability, neuronal differentiation, and embryonal development
Open this publication in new window or tab >>Cannabinoids as modulators of cancer cell viability, neuronal differentiation, and embryonal development
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Effekter av cannabinoider på cancerceller, neuronal differentiering och embryonal utveckling
Abstract [en]

Cannabinoids (CBs) are compounds that activate the CB1 and CB2 receptors. CB receptors mediate many different physiological functions, and cannabinoids have been reported to decrease tumor cell viability, proliferation, migration, as well as to modulate metastasis.

In this thesis, the effects of cannabinoids on human colorectal carcinoma Caco-2 cells (Paper I) and mouse P19 embryonal carcinoma (EC) cells (Paper III) were studied.  In both cell lines, the compounds examined produced a concentration- and time-dependent decrease in cell viability. In Caco-2-cells, HU 210 and the pyrimidine antagonist 5-fluorouracil produced synergistic effects upon cell viability. The mechanisms behind the cytocidal effects of cannabinoids appear to be mediated by other than solely the CB receptor, and a common mechanism in Caco-2 and P19 EC cells was oxidative stress. However, in P19 EC cells the CB receptors contribute to the cytocidal effects possibly via ceramide production.

In paper II, the association between CB1 receptor immunoreactivity (CB1IR) and different histopathological variables and disease-specific survival of colorectal cancer (CRC) was investigated. In microsatellite stable (MSS) cases there was a significant positive association of the tumor grade with the CB1IR intensity. A high CB1IR is indicative of a poorer prognosis in MSS with stage II CRC patients.

Paper IV focused on the cytotoxic effects of cannabinoids during neuronal differentiation. HU 210 affected the cell viability, neurite formation and produced a decreased intracellular AChE activity. The effects of cannabinoids on embryonic development and survival were examined in Paper V, by repeated injection of cannabinoids in fertilized chicken eggs. After 10 days of incubation, HU 210 and cannabidiol (without CB receptor affinity), decreased the viability of chick embryos, in a manner that could be blocked by α-tocopherol (antioxidant) and attenuated by AM251 (CB1 receptor antagonist).

In conclusion, based on these studies, the cannabinoid system may provide a new target for the development of drugs to treat cancer such as CRC. However, the CBs also produce seemingly unspecific cytotoxic effects, and may have negative effects on the neuronal differentiation process. This may be responsible for, at least some of, the embryotoxic effects found in ovo, but also for the cognitive and neurotoxic effects of cannabinoids in the developing and adult nervous system.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2012. 48 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1474
Cannabinoids, cell viability, neuronal differentiation, colorectal cancer, chick embryo
National Category
Pharmacology and Toxicology
Research subject
biokemisk farmakologi; Toxicology
urn:nbn:se:umu:diva-51560 (URN)978-91-7459-358-7 (ISBN)
Public defence
2012-02-24, Sal E04, by 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
Available from: 2012-02-03 Created: 2012-01-26 Last updated: 2012-02-27Bibliographically approved

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Gustafsson, Sofia BPalmqvist, RichardHenriksson, Maria LDahlin, Anna MEdin, SofiaJacobsson, Stig OPÖberg, ÅkeFowler, Christopher J
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