Clues to Cancer Pathogenesis Found in Cell-Conditioned Media
Twenty proteins specifically secreted by
primary effusion lymphoma (PEL) cell lines identified according to new research
published in The American Journal of Pathology
Philadelphia, PA, February 10, 2014
Primary effusion lymphoma (PEL) is a rare B-cell neoplasm
distinguished by its tendency to spread along the thin serous membranes that
line body cavities without infiltrating or destroying nearby tissue. By growing
PEL cells in culture and analyzing the secretome (proteins secreted into
cell-conditioned media), investigators have identified proteins that may
explain PEL pathogenesis, its peculiar cell adhesion, and migration patterns.
They also recognized related oncogenic pathways, thereby providing rationales
for more individualized treatment. The results are published in The American
Journal of Pathology.
A biomarker is a biological molecule found in blood, other
body fluids, or tissues that is a sign of a normal or abnormal process, a
condition, or disease, and can help develop personalized therapeutic approaches
for patients. Analysis of secretomes is a new strategy for discovering
biomarkers involved in cancer pathogenesis based on the reasoning that these
fluids will be enriched in proteins secreted by cancer cells, shed from cancer
cell surfaces, or released from the interior of cells (through vesiculation,
cell lysis, apoptosis, or necrosis). The content of the secretome may reflect
the functional state of the cells at a specific time point.
In this study, investigators from the Istituto Nazionale dei
Tumori of Milan and the Centro di Riferimento Oncologico of Aviano, Italy,
analyzed secretomes from four established PEL cell lines (CRO-AP2, CRO-AP3,
CRO-AP5, and CRO-AP6; established in the laboratories directed by Antonino
Carbone, MD) as well as from four PEL clinical samples and three primary solid
lymphomas. PEL tumor cells are characterized by Kaposi's sarcoma-associated
herpesvirus (KSHV) infection, and the primary solid lymphomas were also KSHV-positive.
Protein content was measured using two complementary mass
spectrometry platforms. The experiments allowed cells to grow for 16 to 18
hours and were performed under serum-free conditions to increase the ability to
detect secreted proteins. Of 266 identified proteins, 139 (52%) were secreted
and 127 were considered to have an intracellular origin or were secreted in an
unconventional fashion. "Most of the proteins we recognized in the secretome of
PEL are new with respect to previous studies utilizing conventional proteomic
analysis and gene expression profiling," said Annunziata Gloghini, PhD, of the
Department of Pathology of the Fondazione IRCCS, Istituto Nazionale dei Tumori,
Milan, Italy.
"Importantly, 27 proteins were shared by secretomes from all
PEL cell lines," added Dr. Gloghini. The researchers found that the PEL
secretomes were enriched with proteins specifically involved in inflammation
and the immune response (eg, HMGB1, GRAA, and PCBP2) and cell growth (eg, LEG1,
STMN1, and S10A6). Other proteins play roles in mRNA processing (eg, ANM1 and
PCBP2) or cell structure, adhesion, migration, and organization (eg, EZRI,
MOES). Some proteins have enzymatic activity (eg, CATA and GSTK1).
Comparison of secretomes from PEL with those from other
tumor cell lines identified 20 proteins specific to the PEL cell lines. This
suggests that secretome profiling provides a source of tumor biomarkers and may
ultimately improve patient management.
The investigators also investigated the association between
the proteins found in the PEL secretome and biological function. Using
pathway/network enrichment analysis, they found that the pathways most
activated in PEL cell lines were involved with regulation of autophagy (an
intracellular catabolic mechanism) through LRRK2-mediated signaling pathways
and with apoptosis and survival through granzyme A signal. "The extracellular
functions of granzyme A might be involved in the particular tropism of PEL and
its cell growth," says Italia Bongarzone, PhD, of the Department of
Experimental Oncology and Molecular Medicine of the Fondazione IRCCS, Istituto
Nazionale dei Tumori, Milan, Italy. "Further studies are needed to confirm and
validate the importance of these pathways/processes and their roles in lymphoma
tumorigenesis and progression."
# # #
Notes for editors
"Primary Effusion Lymphoma: Secretome analysis
reveals novel candidate biomarkers with potential pathogenetic significance,"
by Annunziata Gloghini, Chiara C. Volpi, Dario Caccia, Ambra V. Gualeni, Anna
M. Cilia, Antonino Carbone, and Italia Bongarzone (DOI: http://dx.doi.org/10.1016/j.ajpath.2013.11.028), The
American Journal of Pathology, Volume 184, Issue 3 (March 2014) published by
Elsevier.
Full text of the article is available to credentialed
journalists upon request; contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com. Journalists
wishing to interview the authors should contact:
SEC Relazioni Pubbliche e Istituzionali srl
Carla Castelli at +39 02 6249991 or +339 5771777 (cell)
Giulia Colombo at +39 02 6249991 or +338 4737984 (cell)
ufficiostampa.int@secrp.it
This work was supported by in part by a Grant from the
Ministero della Salute, Rome, within the framework of the "Progetto Integrato
Oncologia-Advanced Molecular Diagnostics" project (RFPS-2006-2-342010.7) (to
Antonino Carbone) and by a grant from Centro di Riferimento Oncologico Aviano
for an intramural project "Agenti Infettivi e Tumori" (to Antonino Carbone).
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