Introductions and Objectives. The complement component
C1q has been shown to be abundantly expressed in the
microenvironment of several solid tumors where it can act
as a tumor-promoting factor favoring adhesion, migration,
and proliferation of cancer cells as well as angiogenesis and
metastasis.In this study, we dissected the non-convectional function of C1q within the microenvironment of malignant pleural
mesothelioma (MPM), a highly aggressive asbestos-related neoplasm, and in particular its role in regulating of human macrophage polarization. Within the MPM environment, C1q has been shown to be able to induce M2-like polarization
of macrophages.
Materials and Methods. The presence of C1q was evaluated
in the microenvironment of MPM human sections
by semiquantitative immunohistochemical analysis. Human
mesothelioma cells were also isolated from pleural biopsies,
characterized by immunofluorescence, cytofluorimetric
analysis and their production of cytokines was evaluated by
qPCR and ELISA. Cells were used for adhesion and migration
experiments. Human Mφ were incubated with MPM conditioned
medium and their phenotype and production of C1q
were evaluated by qPCR. Finally, by immunohistochemical
analyses, the expression of the CD163 M2-like marker was
evaluated.
Results. C1q was variably expressed in the stromal microenvironment
of different mesothelioma histotypes, showing
a higher expression in the epithelioid variant. The pattern
distribution of C1q was consistent with its expression in
tumor-infiltrating myeloid elements, whereas mesothelioma
cells proved to be consistently negative. C1q was able
to induce adhesion and proliferation of neoplastic cells via
enhancement of ERK1/2, SAPK/JNK, and p38 phosphorylation.
Our PCR data suggested that macrophages treated with
MPM conditioning medium showed an M2-like phenotypicprofile (CD206 and IL-10 upregulation) characterized by the
significant upregulation of C1q production. Furthermore,
immunohistochemical analyses confirmed the conspicuous
expression of the M2-like marker CD163 by MPM-infiltrating
macrophages.
Conclusions. C1q was highly expressed in MPM and enhanced
malignant cell adhesion and proliferation. Human
mesothelioma cells increased the C1q production ability by
macrophages. In MPM, C1q may be involved in the M2-
like polarization of macrophages eventually favoring an
anti-inflammatory microenvironment and promoting tumor
progression. Our data identify C1q as a relevant macrophageassociated
marker potentially involved in the invasion and immune
escape of MPM clones and open a new prospect about
interfering with non-conventional complement functions in
this pathological setting.
