Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases

Abstract

MethodsFc:TβRII and transgenic mice. Fc:TβRII has been described previously (11). FVB MMTV-Polyomavirus middle T antigen (MMTV-PyV mT) mice (13) (The Jackson Laboratories, Bar Harbor, Maine, USA) were housed in the Animal Care Facility at Vanderbilt University following The American Association for the Accrediation of Laboratory Animal Care guidelines. Three-week-old transgenic mice were treated twice weekly with Fc:TβRII in PBS (5 mg/kg) by intraperitoneal injection. At 110 days, tissues were harvested and fixed in formalin or were snap-frozen. Serum levels of Fc:TβRII were measured by TGF-βs are potent inhibitors of epithelial cell proliferation. However, in established carcinomas, autocrine/paracrine TGF-β interactions can enhance tumor cell viability and progression. Thus, we studied the effect of a soluble Fc:TGF-β type II receptor fusion protein (Fc:TβRII) on transgenic and transplantable models of breast cancer metastases. Systemic administration of Fc:TβRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice. However, Fc:TβRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases. These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation. Fc:TβRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice. Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TβRII. Therefore, blockade of TGF-β signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas.

TGF-β antagonists: Why suppress a tumor suppressor?

“…Taken together, the two papers (7,8) show that soluble Fc:TβRII is efficacious in reducing tumor metastasis, whether delivered genetically from within the neoplastic cell or administered as an injectable circulating drug. Both groups also addressed the mechanisms of action of Fc:TβRII in attenuating metastatic spread.…”

“…As discussed in the two articles in this issue of the JCI (7,8), the concept of using soluble protein antagonists that bind and inactivate extracellular TGF-β was first tested over a decade ago using decorin, a natural inhibitor of TGF-β, in a therapeutic model for fibrosis (8). More recently, the chimeric Fc:TβRII protein used in the current studies has proved attractive because of its high affinity for TGF-β, its ready purification by protein A affinity chromatography, and its effectiveness in a number of models of fibrosis.…”

“…In response to elevated TGF-β levels, the tumor cell becomes more migratory and invasive. Indeed, in cooperation with activated Ras, TGF-β1 can induce a complete epithelioid-tofibroblastoid transition in both mammary and keratinocyte-derived tumors (1)(2)(3)6), and it can drive metastasis of epithelioid tumors (6)(7)(8)12). TGF-β can also stimulate tumor angiogenesis, alter the stromal environment, and cause local and systemic immunosuppression, all of which contribute to tumor progression and metastasis (1-3).…”

“…The articles in this issue of the JCI (7,8) have pushed the story two steps further, firstly by applying soluble Fc:TβRII as an injectable drug to prove efficacy in suppression of breast tumor metastasis in vivo (7), and secondly by screening for any adverse effects on the mice after lifetime exposure to high-level circulating Fc:TβRII (8). Muraoka et al (7), using the MMTV-PyV mT transgenic model of mammary tumorigenesis, show that twice-weekly intraperitoneal injection of Fc:TβRII reduces lung metastasis tenfold.…”

“…A large number of papers have provided strong evidence for a role of TGF-β in tumor invasion and/or metastasis (1)(2)(3)(4)(5)(6). Now, two papers in this issue of the JCI highlight this clinically significant action of TGF-β in tumorigenesis and provide very encouraging results regarding both the efficacy and the low toxicity of a soluble TGF-β receptor antagonist that effectively reduces tumor spread (7,8).…”