Targeting Transmembrane TNF-α Suppresses Breast Cancer Growth

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 13; pp. 4061 - 4074
• Main Authors: Yu, Mingxia, Zhou, Xiaoxi, Niu, Lin, Lin, Guohong, Huang, Jin, Zhou, Wenjing, Gan, Hui, Wang, Jing, Jiang, Xiaodan, Yin, Bingjiao, Li, Zhuoya
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2013
• Subjects: Animals; Antibodies, Monoclonal, Murine-Derived - pharmacology; Antibody-Dependent Cell Cytotoxicity; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Female; Gynecology. Andrology. Obstetrics; Humans; Lymphatic Metastasis; Mammary gland diseases; MCF-7 Cells; Medical sciences; Membrane Proteins - immunology; Membrane Proteins - metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pharmacology. Drug treatments; Signal Transduction; Tumor Burden - drug effects; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism; Tumors; Xenograft Model Antitumor Assays; Mammary gland diseases; Target; Breast disease; Targeting; Growth; Cytokine; Breast cancer; Malignant tumor; Tumor necrosis factor α; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-3946

TNF antagonists may offer therapeutic potential in solid tumors, but patients who have high serum levels of TNF-α fail to respond to infliximab, suggesting consumption of the circulating antibody and loss of transmembrane TNF-α (tmTNF-α) on tumors by ectodomain shedding. Addressing this possibility, we developed a monoclonal antibody (mAb) that binds both full-length tmTNF-α and its N-terminal truncated fragment on the membrane after tmTNF-α processing but does not cross-react with soluble TNF-α. We documented high levels of tmTNF-α expression in primary breast cancers, lower levels in atypical hyperplasia or hyperplasia, but undetectable levels in normal breast tissue, consistent with the notion that tmTNF-α is a potential therapeutic target. Evaluations in vitro and in vivo further supported this assertion. tmTNF-α mAb triggered antibody-dependent cell-mediated cytotoxicity against tmTNF-α-expressing cells but not to tmTNF-α-negative cells. In tumor-bearing mice, tmTNF-α mAb delayed tumor growth, eliciting complete tumor regressions in some mice. Moreover, tmTNF-α mAb inhibited metastasis and expression of CD44v6, a prometastatic molecule. However, the antibody did not activate tmTNF-α-mediated reverse signaling, which facilitates tumor survival and resistance to apoptosis, but instead inhibited NF-κB activation and Bcl-2 expression by decreasing tmTNF-α-positive cells. Overall, our results established that tmTNF-α mAb exerts effective antitumor activities and offers a promising candidate to treat tmTNF-α-positive tumors, particularly in patients that are nonresponders to TNF antagonists.