Untitled - Red Temática de investigación cooperativa en cáncer

P-12
HETEROGENEITY OF CANCER-ASSOCIATED FIBROBLASTS FROM HUMAN
PRIMARY COLON TUMORS IN THEIR PRO-TUMOROGENIC ABILITIES ON
CANCER CELLS
HERRERA M 1 , HERRERA A 1 , B.M.M.K. ISLAM A 2 , BONILLA F 1 , PEÑA C 1
1
HOSPITAL U. PUERTA DE HIERRO-MAJADAHONDA (RD06/0020/0020)
2
UNIVERSIDAD DE DHAKA, DHAKA 1000, BANGLADESH
Cancer associated-fibroblasts (CAFs) constitute the major component of the tumor stroma.
CAFs actively participate in reciprocal communication with the tumor cells and with other
cell types of the microenvironment, contributing to a tumor-permissive neighborhood and
promoting tumor progression. The aim of this study is the characterization of CAFs from
primary human colon tumors regarding their ability to promote tumorogenesis.
Primary CAFs cultures were established from 15 primary human colon tumors. Purity of
primary fibroblast was evaluated by the expression of different epithelial and myofibroblasts
specific markers by RT-PCR and inmunofluorescence. CAFs were co-cultured with LIM1215
and SW480-ADH tumor colon cells to evaluate their abilities to induce migration. Also,
collagen gel contraction capacity and the expression of putative stem cell markers were
examined in different fibroblast cultures. For further classification, gene expression profile
was analyzed by microarray analysis.
Heterogeneity of α-sma expression was observed in established primary colon CAFs among
different individuals. Co-culture assays of primary CAFs with tumor colon cells showed
significant differences of fibroblasts-derive paracrine pro-migratory effects on cancer cells.
Thus, primary CAFs were grouped regarding their ability to promote tumor migration. Also,
an association between collagen gel contraction and pro-migratory effects of primary CAFs
was observed. Preliminary results from microarray data, α-sma expression and stem cells
markers analyzed indicated association between the groups based on the information of
gene expression and the different promoting migration groups.
The CAFs population from the colon tumor microenvironment is heterogeneous regarding
different patients presenting different pro-tumorogenic abilities, providing us the chance to
search for new cross-talk mediators between fibroblasts and tumor cells that finally could
be blocked to inhibit tumor progression.
P-13
ACADESINE EXERTS ANTITUMORAL ACTIVITY AND COOPERATES WITH
RITUXIMAB IN IN VITRO AND IN VIVO MODELS OF MANTLE CELL
LYMPHOMA
MONTRAVETA A 1 , CAMPO E 2 , ROUÉ G 1 , COLOMER D 1
1
HOSPITAL CLÍNIC-IDIBAPS, BARCELONA (RD06/0020/0014)
2
HOSPITAL CLÍNIC-IDIBAPS, BARCELONA (RD06/0020/0039)
Mantle cell lymphoma (MCL) is an aggressive B-cell neoplasm characterized by the t(11;14)
(q13:q32) that involves cyclin D1 overexpression. Tipically, MCL is characterized by relative
short survival, and poor outcome. Despite this, some cases displays non-nodal leukemic
disease with predominantly hypermutated IgVH, non-complex karyotypes and low or no
expression of SOX11. This indolent variant (iMCL) shows a less aggressive clinical course
that might be managed more conservatively than the conventional subtype (cMCL), which
treatment remains a challenge. Acadesine is a nucleoside analogue initially developed as a
cardioprotective agent, and which has shown a wide range of metabolic effects, including
the activation of AMP-activated protein kinase (AMPK). Acadesine was reported to induce
apoptosis in primary cells from several B lymphoid neoplasms and has been finished powerfully
a phase I/II clinical trial with relapsed/refractory chronic lymphocytic leukemia (CLL)
patients.
To evaluate the antitumoral properties of acadesine in MCL, we exposed a set of 15 MCL
primary cultures and 9 MCL cell lines for up to 48h with increasing doses of the drug. In
both MCL cell lines and MCL primary cultures, we observed a heterogeneous response,
with no correlation to common genetic alterations. Among MCL primary cultures, Acadesine
showed selective cytotoxic activity against malignant B cells while sparing accompanying T
cells. Of note, those cases corresponding to iMCL group showed increased sensitivity to the
drug, when compared to conventional MCL cases (p=0.014).
In drug combination assays, Acadesine showed a synergistic effect when combined with
the anti-CD20 monoclonal antibody Rituximab. The Acadesine-Rituximab combination also
blocked tumor growth in a cell line derived xenograft mouse model. By performing gene
profile analysis of these tumors, we found that the combination down-regulates signatures
related with cell cycle, inflammatory response and cell proliferation, suggesting that
Acadesine-Rituximab combination may represent a new approach for this entity.
Observaciones: This work was supported by grants from Ministerio de Ciencia y Innovación
(SAF 09/9503) (to DC), Redes Temáticas de Investigacion Cooperativa de Cáncer from
the Instituto de Salud Carlos III (RED 2006-20-014 and 079) (to DC and EC), and Fondo de
Investigación Sanitaria (CP07/00072 and PI09/00060) (to GR). AM is the recipient of a FPI
pre-doctoral fellowship from Ministerio de Ciencia e Innovación.
The laboratory expenses of this study were covered in part by a research contract from
Advancell Therapeutics, Advancell-Advanced In Vitro Cell Technologies S.A.
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