Breast cancer is one of the leading causes of death amongst
Western women. Although the mortality rates associated with this disease are
decreasing, the need for new therapies is obvious because most recurrences are
lethal and certain cases remain reluctant to conventional treatments. It has
been demonstrated that cannabinoids induce antiproliferative, antiangiogenic and
antimetastatic effects in several animal models of cancer, which make them
potential antitumoral agents.
effect of cannabinoids on breast cancer.
Our work has demonstrated that cannabinoids
reduce human breast cancer cell proliferation and induce cancer
cell death by apoptosis. The study of the molecular mechanisms
underlying this effect has allowed us to propose a model that
includes the blockade of the cell cycle in the transition from
G2 to mitosis and the inhibition of the JunD transcription
factor, a member of the AP-1 family.
effect of cannabinoids in vivo.
Although the antitumoral action of cannabinoids
has been demonstrated in different models of cancer, most of
them are based on xenografts, which are useful but limited
tools. These models rely on the propagation of tumor cells in
immunodeficient mice at ectopic or orthotopic sites and lack
crucial features of patients’ tumors such as the actual tumor
architecture and the interactions with the tumor
microenvironment, including normal non-cancerous surrounding
tissue, vasculature and immune cells. We are currently using a
genetically engineered animal model of breast cancer to analyze
the effect of cannabinoids on tumor progression and generation.
effect mediated by non-psychotropic cannabinoid receptors.
It is known that cannabinoids exert a number of
psychotropic actions, which make difficult to use them in the
clinic. However, most of these effects are mediated by CB1
receptors exclusively. Thus, the selective activation of other
cannabinoid receptors different than CB1 would be an
alternative strategy to evoke their therapeutic effects. Our
data show that CB2 receptor mediates the antitumoral
effect of cannabinoids on breast cancer. Moreover, we have
observed a correlation between CB2 expression and
tumor malignancy. We are currently generating mice with two
genetic manipulations (transgenic for neu oncogen plus CB2
knock-out) to understand the involvement of this receptor in
oncogenesis and tumor progression.
effect mediated by other cannabinoid receptors.
There is evidence pointing to the existence of cannabinoid
receptors other than CB1 and CB2.
Preliminary data obtained in our group point to the
participation of some of them in the effect of cannabinoids on
cancer cell proliferation, not only in breast cancer but in many
type of tumors. We are currently analyzing this participation by
both in vitro and in vivo approaches.
C. Sánchez, M.L. Cortés, T. Gómez del Pulgar, M.
Izquierdo, M. Guzmán
Antitumoral action of cannabinoids: involvement of sustained
ceramide accumulation and extracellular signal-regulated kinase
Nat. Med. 6,
M.L. de Ceballos, T. Gómez del Pulgar, D. Rueda, C. Corbacho, G.
Velasco, I. Galve-Roperh, J.W. Huffman, S. Ramón y Cajal, M.
Inhibition of glioma growth in vivo by selective
activation of the CB2 cannabinoid receptor
Cancer Res. 61,
M.M. Caffarel, D.
Sarrió, J. Palacios, M. Guzmán, C.
inhibits cell cycle progression in human breast cancer cells
through Cdc2 regulation
66, 6615-6621 (2006)
M.M. Caffarel, G.
Moreno-Bueno, C. Cerutti, J. Palacios, M. Guzmán, F. Mechta-Grigoriou,
JunD is involved in
antiproliferative effect on human breast cancer cells
Caffarel, C. Andradas, E. Mira, C. Cerutti, J.M. Flores, G.
Moreno-Bueno, I. García-Real, J. Palacios, S. Mañes, M. Guzmán,
Cannabinoids reduce ErbB2-driven breast cancer progression
through Akt inhibition
9, 196 (2010)
C. Andradas, M.M. Caffarel, E.
Pérez-Gómez, M. Salazar, M. Lorente, G. Velasco, M. Guzmán, C.
The orphan G protein-coupled
receptor GPR55 promotes cancer cell proliferation via ERK
Oncogene (aceptado, 2010)
In order to carry out our projects, we use a multidisciplinary
methodology which includes biochemical and pharmacological
approaches, molecular biology tools, and the use and generation
of genetically modified animal models. In particular, we analyze
gen and protein expression by semiquantitative and quantitative
PCR and DNA arrays (genes) and Western blotting and
immunofluorescence (proteins), we modulate the expression of
proteins with plasmids, adeno- and retroviruses (overexpression)
and small interference RNA (silencing), we use different in
vitro (cell culture) and in vivo (ecto- and orthotopic
xenografts in immune-deficient mice, transgenic mice) models of
Our group actively collaborates with other labs.
Here there is a list of some of them:
Andrew Irving, Universidad de Dundee, Dundee,
Santos Mañes, Centro Nacional de
Biotecnología, Madrid, España:
Fatima Mechta-Grigoriou, Instituto Marie
Curie, Paris, Francia:
Gema Moreno, Instituto de Investigaciones
Biomédicas “Alberto Sols”, Madrid, España:
Maria Waldhoer, Universidad de Graz, Graz,