Eletters

Topic:

Response to Chakroborty et. al.

Rivka Inzelberg | inzelber@post.tau.ac.il

The Sagol Neuroscience Center, Sheba Medical Center

We have read with interest the article by Chakroborty et al (1), entitled "Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization". The authors found a significant decrease in bone marrow dopamine in tumor-bearing mice and increased mobilization of endothelial progenitor cells (EPC) associated with tumor neo-vascularization. Dopamine treatment, by activating D2 receptors, inhibited EPC mobilization and tumor growth by the suppressing the vascular endothelial growth factor (VEGFA) induced ERK1/ERK2 phosphorylation.

The link between VEGF and dopamine may be potentially important in the development of dopaminergic agents for the treatment of cancer.

The link between dopamine and its potential anti-cancer effect is not fully understood but some insights may be derived from the observation that Parkinson disease (PD) patients show low rates of certain cancers (2, 3). This inverse relationship between PD and some cancers may be possibly related to common PD-related genes, such as parkin and PINK-1 (PTEN-induced kinase 1) that are also tumor suppressor genes(2). A second possible mechanism is autophagy-lysosomal pathway abnormalities which are involved in both diseases(4). A third mechanism could be the inhibitory effect of dopamine on tumor growth as noted by Chakroborty et al.(1). Is it is possible that dopamine and/or dopamine agonists induce VEGF suppression and thus reduce tumor growth rates or consequently lower the risk of cancer in patients with PD? This latter mechanism is supported by the recent observation that dopamine increases the efficacy of anticancer drugs in breast and colon cancer in mice models(5). It is likely that different mechanisms play a role in the relationship between PD and cancer since not all cancers are less frequent in PD patients. Besides melanomas (2, 6), other cancers may occur at higher frequency in certain populations of patients with PD.

Strongosky et al(7) followed a large family with PARK8 parkinsonism (LRRK2, R1441C) and found that four of the 18 members known LRRK2 mutation had colon cancer.

There are at least two pathways involved in cell survival that involve products of genes associated with PD(2): 1. the mitogen-activated protein kinases (MAPK) (Erk1/2) signaling pathway and 2. the PI3K/Akt dependent pathway. The LRRK2 gene encodes a MAPKKK protein(8, 9), but its potential influence in tumor growth remains to be elucidated. Better understanding of the relationship between PD and cancers may provide insights into the treatment of both diseases.

Rivka Inzelberg, MD ^1,2 and Joseph Jankovic, MD ³

¹ The Sagol Neuroscience Center, Department of Neurology, Sheba Medical Center, Tel Hashomer and ² Rappaport Faculty of Medicine, Technion, Haifa, Israel ³ Baylor College of Medicine, Department of Neurology, Houston Texas, USA

The authors have no conflict of interest.

Address for correspondence: Rivka Inzelberg, MD, The Sagol Neuroscience Center, Department of Neurology, Sheba Medical Center, Tel Hashomer, 52621, Tel/Fax: +972-3-5304718, e-mail: inzelber@post.tau.ac.il cc to rivka.inzelberg@gmail.com

References

1. Chakroborty, D., Chowdhury, U.R., Sarkar, C., Baral, R., Dasgupta, P.S., and Basu, S. 2008. Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization. J Clin Invest 118:1380-1389.

2. Inzelberg, R., and Jankovic, J. 2007. Are parkinson disease patients protected from some but not all cancers? Neurology 69:1542-1550.

3. Inzelberg, R., and Jankovic, J. 2008. Are parkinson disease patients protected from some but not all cancers? Neurology.Letter in press.

4. Pan, T., Kondo, S., Le, W., and Jankovic, J. 2008. The role of autophagy-lysosome pathway in neurodegeneration associated with parkinson's disease. Brain.

5. Sarkar, C., Chakroborty, D., Chowdhury, U.R., Dasgupta, P.S., and Basu, S. 2008. Dopamine increases the efficacy of anticancer drugs in breast and colon cancer preclinical models. Clin Cancer Res 14:2502-2510.

6. Inzelberg, R., Rabey, J.M., Djaldetti, R., Reches, A., Badarny, S., Hassin-Baer, S., Trau, H., Aharon-Peretz, J., Huberman, M., Gilead, L., et al. 2007. Elevated prevalence of malignant melanoma in israeli patients with parkinson's disease. Mov Disord 22:S167.

7. Strongosky, A.J., Farrer, M., and Wszolek, Z.K. 2008. Are parkinson disease patients protected from some but not all cancers? Neurology.Letter (in press).

8. Deng, H., Le, W., Guo, Y., Hunter, C.B., Xie, W., Huang, M., and Jankovic, J. 2006. Genetic analysis of LRRK2 mutations in patients with parkinson disease. J Neurol Sci 251:102-106.

9. Tomiyama, H., Li, Y., Funayama, M., Hasegawa, K., Yoshino, H., Kubo, S., Sato, K., Hattori, T., Lu, C.S., Inzelberg, R., et al. 2006. Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries. Mov Disord 21:1102-1108.