IL-7 up-regulates TNF-alpha-dependent osteoclastogenesis in patients affected by solid tumor.
BACKGROUND
Interleukin-7 (IL-7) is a potent regulator of lymphocyte development, which has also significant effects on bone; in fact it is a potent osteoclastogenic factor. Some human solid tumors produce high IL-7 levels, suggesting a potential IL-7 role on tumor development and progression.


METHODS
We studied 50 male patients affected by solid tumors, and their blood samples were collected at tumor diagnosis. PBMCs were isolated and cultured with/without IL-7 to study its influence on osteoclastogenesis. Serum and cell culture supernatant IL-7 levels were measured by ELISA. The quantitative analysis of IL-7 expression on T and B cells was performed by Real-Time PCR.


RESULTS
Serum IL-7 levels were highest in osteolytic cancer patients, followed by cancer patients without bone lesions, and then healthy controls. We showed the IL-7 production in PBMC cultures and particularly in monocyte and B cell co-cultures. A quantitative analysis of IL-7 expression in T and B cells confirmed that B cells had a high IL-7 expression. In all cell culture conditions, IL-7 significantly increased osteoclastogenesis and an anti-IL-7 antibody inhibited it. We demonstrated that IL-7 supports OC formation by inducing the TNF-alpha production and low RANKL levels, which synergize in promoting osteoclastogenesis.


CONCLUSIONS
We demonstrated the presence of high serum IL-7 levels in patients with bone metastasis, suggesting the use of serum IL-7 level as a clinical marker of disease progression and of bone involvement. Moreover, we showed the capability of IL-7 to stimulate spontaneous osteoclastogenesis of bone metastatic patients and to induce osteoclastogenesis in cancer patients without bone involvement. These findings add further details to the disclosure of the mechanisms controlling bone metastasis in solid tumors.
Roato
Ilaria
I
Center for Experimental Research and Medical Studies (CeRMS), University and AZO San Giovanni Battista, Turin, Italy; Department of Medical Oncology, University and AZO San Giovanni Battista, Turin, Italy. roato78@libero.it
Brunetti
Giacomina
G
Gorassini
Eva
E
Grano
Maria
M
Colucci
Silvia
S
Bonello
Lisa
L
Buffoni
Lucio
L
Manfredi
Roberto
R
Ruffini
Enrico
E
Ottaviani
Davide
D
Ciuffreda
Libero
L
Mussa
Antonio
A
Ferracini
Riccardo
R
D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000502:physiology; D001859:Bone Neoplasms / Q000097:blood / Q000473:pathology / Q000556:secondary; D001862:Bone Resorption / Q000097:blood / Q000209:etiology / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D015851:Interleukin-7 / Q000097:blood / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology; D009369:Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology*; D053245:RANK Ligand / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
C508605:IL7 protein, human; D015851:Interleukin-7; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha