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Therapeutic effects of anti-CD115 monoclonal antibody in mouse cancer models through dual inhibition of tumor-associated macrophages and osteoclasts.

Fend L, Accart N, Kintz J, Cochin S, Reymann C, Le Pogam F, Marchand JB, Menguy T, Slos P, Rooke R, Fournel S, Bonnefoy JY, Préville X, Haegel H - PLoS ONE (2013)

Bottom Line: As shown by immunohistochemistry, this therapeutic effect correlated with the depletion of F4/80(+)CD163(+) M2-polarized TAMs. In a breast cancer model of bone metastasis, the anti-CD115 mAb potently blocked the differentiation of osteoclasts and their bone destruction activity.This resulted in the inhibition of cancer-induced weight loss.CD115 thus represents a promising target for cancer immunotherapy, since a specific blocking antibody may not only inhibit the growth of a primary tumor through TAM depletion, but also metastasis-induced bone destruction through osteoclast inhibition.

View Article: PubMed Central - PubMed

Affiliation: Transgene, Illkirch-Graffenstaden, France.

ABSTRACT
Tumor progression is promoted by Tumor-Associated Macrophages (TAMs) and metastasis-induced bone destruction by osteoclasts. Both myeloid cell types depend on the CD115-CSF-1 pathway for their differentiation and function. We used 3 different mouse cancer models to study the effects of targeting cancer host myeloid cells with a monoclonal antibody (mAb) capable of blocking CSF-1 binding to murine CD115. In mice bearing sub-cutaneous EL4 tumors, which are CD115-negative, the anti-CD115 mAb depleted F4/80(+) CD163(+) M2-type TAMs and reduced tumor growth, resulting in prolonged survival. In the MMTV-PyMT mouse model, the spontaneous appearance of palpable mammary tumors was delayed when the anti-CD115 mAb was administered before malignant transition and tumors became palpable only after termination of the immunotherapy. When administered to mice already bearing established PyMT tumors, anti-CD115 treatment prolonged their survival and potentiated the effect of chemotherapy with Paclitaxel. As shown by immunohistochemistry, this therapeutic effect correlated with the depletion of F4/80(+)CD163(+) M2-polarized TAMs. In a breast cancer model of bone metastasis, the anti-CD115 mAb potently blocked the differentiation of osteoclasts and their bone destruction activity. This resulted in the inhibition of cancer-induced weight loss. CD115 thus represents a promising target for cancer immunotherapy, since a specific blocking antibody may not only inhibit the growth of a primary tumor through TAM depletion, but also metastasis-induced bone destruction through osteoclast inhibition.

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Progression of mammary tumors in C57BL/6 PyMT mice.Percentile distribution of tumor stages characterized by histopathology. Four to six mammary glands were removed from 2 to 6 PyMT mice at the indicated ages.
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pone-0073310-g003: Progression of mammary tumors in C57BL/6 PyMT mice.Percentile distribution of tumor stages characterized by histopathology. Four to six mammary glands were removed from 2 to 6 PyMT mice at the indicated ages.

Mentions: Transgenic MMTV-PyMT mice, expressing the polyoma middle T oncogene under control of the mouse mammary tumor virus promoter, spontaneously develop mammary tumors with stages comparable to the human situation [16], [39]. Based on the four-stage classification described in PyMT mice bred on a C3H/B6 background by Lin et al [39], we have characterized histologically the progression of mammary tumors in PyMT mice on the C57BL/6 genetic background (Figure 3). At 4 weeks of age, a few mammary glands were hyperplasic with epithelial cells proliferating within acini and forming focal or multifocal clusters on terminal ducts. In addition to the hyperplasia, adenomas (mammary intraepithelial neoplasia MIN) were observed at 6 weeks of age, characterized by solid sheets of proliferating epithelial cells completely filling the acini but still confined by a basement membrane. Foci of leukocytic infiltration were associated with increased vascularization. The initial stage of malignant transition, termed early carcinoma (EC), was first detected starting at 10 weeks of age. EC was characterized by a change in nuclear morphology, the disappearance of basement membranes and high density leukocyte infiltrates surrounding the acini. Mammary tumors became palpable between 13 and 14 weeks of age and on week 16, all mice had palpable tumors. Advanced invasive (late) carcinomas (LC) appeared around 18 weeks of age, characterized by solid sheets of epithelial cells and the loss of acinar structures, with the disappearance of basement membranes and the presence of necrotic areas. LC were always associated with lung metastasis.


Therapeutic effects of anti-CD115 monoclonal antibody in mouse cancer models through dual inhibition of tumor-associated macrophages and osteoclasts.

Fend L, Accart N, Kintz J, Cochin S, Reymann C, Le Pogam F, Marchand JB, Menguy T, Slos P, Rooke R, Fournel S, Bonnefoy JY, Préville X, Haegel H - PLoS ONE (2013)

Progression of mammary tumors in C57BL/6 PyMT mice.Percentile distribution of tumor stages characterized by histopathology. Four to six mammary glands were removed from 2 to 6 PyMT mice at the indicated ages.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3760897&req=5

pone-0073310-g003: Progression of mammary tumors in C57BL/6 PyMT mice.Percentile distribution of tumor stages characterized by histopathology. Four to six mammary glands were removed from 2 to 6 PyMT mice at the indicated ages.
Mentions: Transgenic MMTV-PyMT mice, expressing the polyoma middle T oncogene under control of the mouse mammary tumor virus promoter, spontaneously develop mammary tumors with stages comparable to the human situation [16], [39]. Based on the four-stage classification described in PyMT mice bred on a C3H/B6 background by Lin et al [39], we have characterized histologically the progression of mammary tumors in PyMT mice on the C57BL/6 genetic background (Figure 3). At 4 weeks of age, a few mammary glands were hyperplasic with epithelial cells proliferating within acini and forming focal or multifocal clusters on terminal ducts. In addition to the hyperplasia, adenomas (mammary intraepithelial neoplasia MIN) were observed at 6 weeks of age, characterized by solid sheets of proliferating epithelial cells completely filling the acini but still confined by a basement membrane. Foci of leukocytic infiltration were associated with increased vascularization. The initial stage of malignant transition, termed early carcinoma (EC), was first detected starting at 10 weeks of age. EC was characterized by a change in nuclear morphology, the disappearance of basement membranes and high density leukocyte infiltrates surrounding the acini. Mammary tumors became palpable between 13 and 14 weeks of age and on week 16, all mice had palpable tumors. Advanced invasive (late) carcinomas (LC) appeared around 18 weeks of age, characterized by solid sheets of epithelial cells and the loss of acinar structures, with the disappearance of basement membranes and the presence of necrotic areas. LC were always associated with lung metastasis.

Bottom Line: As shown by immunohistochemistry, this therapeutic effect correlated with the depletion of F4/80(+)CD163(+) M2-polarized TAMs. In a breast cancer model of bone metastasis, the anti-CD115 mAb potently blocked the differentiation of osteoclasts and their bone destruction activity.This resulted in the inhibition of cancer-induced weight loss.CD115 thus represents a promising target for cancer immunotherapy, since a specific blocking antibody may not only inhibit the growth of a primary tumor through TAM depletion, but also metastasis-induced bone destruction through osteoclast inhibition.

View Article: PubMed Central - PubMed

Affiliation: Transgene, Illkirch-Graffenstaden, France.

ABSTRACT
Tumor progression is promoted by Tumor-Associated Macrophages (TAMs) and metastasis-induced bone destruction by osteoclasts. Both myeloid cell types depend on the CD115-CSF-1 pathway for their differentiation and function. We used 3 different mouse cancer models to study the effects of targeting cancer host myeloid cells with a monoclonal antibody (mAb) capable of blocking CSF-1 binding to murine CD115. In mice bearing sub-cutaneous EL4 tumors, which are CD115-negative, the anti-CD115 mAb depleted F4/80(+) CD163(+) M2-type TAMs and reduced tumor growth, resulting in prolonged survival. In the MMTV-PyMT mouse model, the spontaneous appearance of palpable mammary tumors was delayed when the anti-CD115 mAb was administered before malignant transition and tumors became palpable only after termination of the immunotherapy. When administered to mice already bearing established PyMT tumors, anti-CD115 treatment prolonged their survival and potentiated the effect of chemotherapy with Paclitaxel. As shown by immunohistochemistry, this therapeutic effect correlated with the depletion of F4/80(+)CD163(+) M2-polarized TAMs. In a breast cancer model of bone metastasis, the anti-CD115 mAb potently blocked the differentiation of osteoclasts and their bone destruction activity. This resulted in the inhibition of cancer-induced weight loss. CD115 thus represents a promising target for cancer immunotherapy, since a specific blocking antibody may not only inhibit the growth of a primary tumor through TAM depletion, but also metastasis-induced bone destruction through osteoclast inhibition.

Show MeSH
Related in: MedlinePlus