TY - JOUR T1 - C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation. JF - Nat Commun Y1 - 2016 A1 - Bulla, Roberta A1 - Tripodo, Claudio A1 - Rami, Damiano A1 - Ling, Guang Sheng A1 - Agostinis, Chiara A1 - Guarnotta, Carla A1 - Zorzet, Sonia A1 - Durigutto, Paolo A1 - Botto, Marina A1 - Tedesco, Francesco KW - Animals KW - Apoptosis KW - Cell Line, Tumor KW - Cell Movement KW - Cell Proliferation KW - Complement Activation KW - Complement C1q KW - Complement C3 KW - Complement C5 KW - Humans KW - Mice KW - Mice, Inbred C57BL KW - Mice, Knockout KW - Neoplasms AB -

Complement C1q is the activator of the classical pathway. However, it is now recognized that C1q can exert functions unrelated to complement activation. Here we show that C1q, but not C4, is expressed in the stroma and vascular endothelium of several human malignant tumours. Compared with wild-type (WT) or C3- or C5-deficient mice, C1q-deficient (C1qa(-/-)) mice bearing a syngeneic B16 melanoma exhibit a slower tumour growth and prolonged survival. This effect is not attributable to differences in the tumour-infiltrating immune cells. Tumours developing in WT mice display early deposition of C1q, higher vascular density and an increase in the number of lung metastases compared with C1qa(-/-) mice. Bone marrow (BM) chimeras between C1qa(-/-) and WT mice identify non-BM-derived cells as the main local source of C1q that can promote cancer cell adhesion, migration and proliferation. Together these findings support a role for locally synthesized C1q in promoting tumour growth.

VL - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26831747?dopt=Abstract ER - TY - JOUR T1 - C1q as a unique player in angiogenesis with therapeutic implication in wound healing. JF - Proc Natl Acad Sci U S A Y1 - 2014 A1 - Bossi, Fleur A1 - Tripodo, Claudio A1 - Rizzi, Lucia A1 - Bulla, Roberta A1 - Agostinis, Chiara A1 - Guarnotta, Carla A1 - Munaut, Carine A1 - Baldassarre, Gustavo A1 - Papa, Giovanni A1 - Zorzet, Sonia A1 - Ghebrehiwet, Berhane A1 - Ling, Guang Sheng A1 - Botto, Marina A1 - Tedesco, Francesco KW - Animals KW - Cell Proliferation KW - Complement C1q KW - DNA Primers KW - Endothelial Cells KW - Enzyme-Linked Immunosorbent Assay KW - Human Umbilical Vein Endothelial Cells KW - Humans KW - Immunoblotting KW - Immunohistochemistry KW - In Situ Hybridization KW - Mice KW - Mice, Inbred C57BL KW - Mice, Knockout KW - Neovascularization, Physiologic KW - Rats KW - Rats, Wistar KW - Real-Time Polymerase Chain Reaction KW - Wound Healing AB -

We have previously shown that C1q is expressed on endothelial cells (ECs) of newly formed decidual tissue. Here we demonstrate that C1q is deposited in wound-healing skin in the absence of C4 and C3 and that C1q mRNA is locally expressed as revealed by real-time PCR and in situ hybridization. C1q was found to induce permeability of the EC monolayer, to stimulate EC proliferation and migration, and to promote tube formation and sprouting of new vessels in a rat aortic ring assay. Using a murine model of wound healing we observed that vessel formation was defective in C1qa(-/-) mice and was restored to normal after local application of C1q. The mean vessel density of wound-healing tissue and the healed wound area were significantly increased in C1q-treated rats. On the basis of these results we suggest that C1q may represent a valuable therapeutic agent that can be used to treat chronic ulcers or other pathological conditions in which angiogenesis is impaired, such as myocardial ischemia.

VL - 111 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24591625?dopt=Abstract ER - TY - JOUR T1 - An alternative role of C1q in cell migration and tissue remodeling: contribution to trophoblast invasion and placental development. JF - J Immunol Y1 - 2010 A1 - Agostinis, Chiara A1 - Bulla, Roberta A1 - Tripodo, Claudio A1 - Gismondi, Angela A1 - Stabile, Helena A1 - Bossi, Fleur A1 - Guarnotta, Carla A1 - Garlanda, Cecilia A1 - De Seta, Francesco A1 - Spessotto, Paola A1 - Santoni, Angela A1 - Ghebrehiwet, Berhane A1 - Girardi, Guillermina A1 - Tedesco, Francesco KW - Animals KW - Cell Adhesion KW - Chemotaxis, Leukocyte KW - Complement C1q KW - Female KW - Humans KW - Immunoblotting KW - Immunohistochemistry KW - Immunoprecipitation KW - Mice KW - Mice, Inbred C57BL KW - Microscopy, Confocal KW - Placentation KW - Pre-Eclampsia KW - Pregnancy KW - Reverse Transcriptase Polymerase Chain Reaction KW - Trophoblasts AB -

Fetal trophoblast cells invading the decidua in the early phase of pregnancy establish complex interaction with the maternal extracellular matrix. We discovered that C1q was widely distributed in human decidual stroma in the absence of C4 and C3 and was actively synthesized by migrating extravillous trophoblasts. The cells expressed the messages for the three chains of C1q and secreted this complement component that interacted with the proteins of the decidual extracellular matrix. Solid phase-bound C1q promoted trophoblast adhesion and migration, and cell binding to C1q resulted in activation of ERK1/2 MAPKs. Ab inhibition experiments showed that the receptors for the globular head of C1q/p33 and α(4)β(1) integrin were both involved in this process and were colocalized on the cell surface following binding of C1q to trophoblasts. We also found that C1q(-/-) mice manifested increased frequency of fetal resorption, reduced fetal weight, and smaller litter sizes compared with wild-type mice. C1q deficiency was associated with impaired labyrinth development and decidual vessel remodeling. Collectively, these data suggest that C1q plays an important role in promoting trophoblast invasion of decidua and that defective local production of C1q may be involved in pregnancy disorders, such as pre-eclampsia, characterized by poor trophoblast invasion.

VL - 185 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20810993?dopt=Abstract ER -