Extracellular domain of TGFβ type III receptor inhibits angiogenesis and tumor growth in human cancer cells

Bandyopadhyay, Abhik; Zhu, Yong; Malik, Shazli N.; Kreisberg, Jeffrey I.; Brattain, Michael G.; Sprague, Eugene A.; Luo, Jian; López‐Casillas, Fernando; Sun, LuZhe

doi:10.1038/sj.onc.1205439

Cited by 76 publications

(56 citation statements)

References 34 publications

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“…These strategies fall into two classes: direct inhibition of TGF-β (using TGF-β-neutralizing antibodies or TGF-β receptor inhibitors) and interference with downstream signaling (e.g., peroxisome proliferator-activated receptor-γ agonists) (33)(34)(35)(36)(37)(38)(39)(40)(41)(42). In our study, we used two strategies to block TGF-β signaling: (i) in a genetic model, TGF-β signaling was inhibited by stable transfection of tumor cells with a soluble TGF-β receptor (sTβRII), which functions as a "TGF-β trap," competing with TGF-β1 and -β3 for binding to TGF-β receptor ΙΙ; and (ii) in a pharmacologic model, TGF-β signaling was inhibited by a neutralizing antibody that blocks all three isoforms of TGF-β.…”

Section: Discussionmentioning

confidence: 99%

TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma

Liu

Liao

Diop-Frimpong

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

291

234

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Although the role of TGF-β in tumor progression has been studied extensively, its impact on drug delivery in tumors remains far from understood. In this study, we examined the effect of TGF-β blockade on the delivery and efficacy of conventional therapeutics and nanotherapeutics in orthotopic mammary carcinoma mouse models. We used both genetic (overexpression of sTβRII, a soluble TGF-β type II receptor) and pharmacologic (1D11, a TGF-β neutralizing antibody) approaches to block TGF-β signaling. In two orthotopic mammary carcinoma models (human MDA-MB-231 and murine 4T1 cell lines), TGF-β blockade significantly decreased tumor growth and metastasis. TGF-β blockade also increased the recruitment and incorporation of perivascular cells into tumor blood vessels and increased the fraction of perfused vessels. Moreover, TGF-β blockade normalized the tumor interstitial matrix by decreasing collagen I content. As a result of this vessel and interstitial matrix normalization, TGF-β blockade improved the intratumoral penetration of both a low-molecular-weight conventional chemotherapeutic drug and a nanotherapeutic agent, leading to better control of tumor growth.breast cancer | vessel normalization | drug delivery B reast cancer is the second leading cause of cancer death in women, with most fatalities resulting from a failure to control metastatic disease with systemically administered therapies. In addition to the induction of cellular resistance mechanisms (decreased apoptosis, increased drug efflux, etc.), impaired intratumoral drug delivery is an important physiological factor contributing toward chemoresistance (1, 2). TGF-β is an important regulator of normal mammary gland development and function, as well as of the progression of mammary carcinomas (3-8). Although the role of TGF-β in tumor progression and metastasis has been studied extensively, little is known about its impact on drug delivery.Transport of a therapeutic agent from the circulation to cancer cells is a three-step process. Systemically administered drugs must (i) travel to different regions within a tumor via the vascular network; (ii) cross the vessel wall; and finally (iii) diffuse through the interstitial space to reach the tumor cells, with each step being hindered by the presence of an abnormal vasculature and/or matrix (1, 2, 9, 10). Tumor blood vessels are structurally and functionally abnormal, characterized by increased permeability and heterogeneous perfusion. Poor vascular perfusion decreases drug delivery and, as a result, impairs the efficacy of blood-borne antitumor agents (1, 11). In addition, the dense collagen-rich interstitial matrix further hinders drug transport to tumor cells-a feature especially relevant to larger therapeutics, such as nanoparticles (1-100 nm) (1, 10, 12, 13). The dense collagen matrix also contributes to solid stress, which compresses tumor vessels (14). Hence, depleting collagen will reduce stress and open up compressed vessels. TGF-β is a negative regulator of pericyte recruitment during blood vessel stab...

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Section: Discussionmentioning

confidence: 99%

TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma

Liu

Liao

Diop-Frimpong

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

291

234

View full text Add to dashboard Cite

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“…Because Bsp expression in metastases is down-regulated by systemic treatment with anti-TGF-h antibodies, local suppression of Bsp in the tumor cell may contribute to the efficacy of this therapeutic approach. In other model systems, systemic antagonism of TGF-h has been shown to enhance immune surveillance and suppress angiogenesis (7,8,47). Treatment with anti-TGF-h antibodies enhanced the ability of dendritic cell-based vaccines to inhibit the growth of 4T1 primary tumors (48); thus, immune mechanisms are also likely to contribute to the antimetastatic efficacy of TGF-h antagonism in the 4T1 model.…”

Section: Discussionmentioning

confidence: 99%

Bone Sialoprotein Mediates the Tumor Cell–Targeted Prometastatic Activity of Transforming Growth Factor β in a Mouse Model of Breast Cancer

et al. 2006

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Transforming growth factor Bs (TGF-B) play a dual role in carcinogenesis, functioning as tumor suppressors early in the process, and then switching to act as prometastatic factors in late-stage disease. We have previously shown that high molecular weight TGF-B antagonists can suppress metastasis without the predicted toxicities. To address the underlying mechanisms, we have used the 4T1 syngeneic mouse model of metastatic breast cancer. Treatment of mice with a monoclonal anti-TGF-B antibody (1D11) significantly suppressed metastasis of 4T1 cells to the lungs. When metastatic 4T1 cells were recovered from lungs of 1D11-treated and control mice, the most differentially expressed gene was found to be bone sialoprotein (Bsp). Immunostaining confirmed the loss of Bsp protein in 1D11-treated lung metastases, and TGF-B was shown to regulate and correlate with Bsp expression in vitro. Functionally, knockdown of Bsp in 4T1 cells reduced the ability of TGF-B to induce local collagen degradation and invasion in vitro, and treatment with recombinant Bsp protected 4T1 cells from complement-mediated lysis. Finally, suppression of Bsp in 4T1 cells reduced metastasis in vivo. We conclude that Bsp is a plausible mediator of at least some of the tumor celltargeted prometastatic activity of TGF-B in this model and that Bsp expression in metastases can be successfully suppressed by systemic treatment with anti-TGF-B antibodies. (Cancer Res 2006; 66(12): 6327-35)

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“…Tgfbr3, also known as betaglycan, in its soluble form, is a potent antagonist of TGFb, a promoter of angiogenesis. Additionally, expression of the soluble extracellular domain of TGFbr3 inhibits angiogenesis in vivo and in vitro (Bandyopadhyay et al 2002). Therefore, it is likely that the initial increase in Tgfbr3 expression in SD mice represents an inhibition of testicular angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Photoperiod-induced differential expression of angiogenesis genes in testes of adult Peromyscus leucopus

Pyter¹,

Hotchkiss²,

Nelson³

2005

Reproduction

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Non-pathological angiogenesis in adults is rare and is largely thought to be restricted to wound healing and female reproductive cycles. Adult male rodents, however, display seasonal angiogenesis to support seasonal changes in reproductive tissue morphology. Non-tropical rodents use photoperiod (day length) to determine the time of year. During short days, the reproductive system undergoes involution and mating behaviours stop, adaptations which presumably allow energy resources to be shifted to processes necessary for winter survival. We compared the patterns of gene expression involved in angiogenesis in testes of white-footed mice (Peromyscus leucopus) following 7, 14, 21 or 34 weeks of long or short day lengths. Short days decreased body mass, reproductive tract mass and seminiferous tubule diameter. Potential genes involved in seasonal angiogenesis were screened by hybridizing testicular RNA from each group to angiogenesis-specific microarrays. Genes that were $6-fold different between long-and short-day testes (i.e. hypoxia-inducible factor 1a (Hif1a), plasminogen activator inhibitor 1 (Serpine1), transforming growth factor b receptor 3 (Tgfbr3) and tumour necrosis factor (Tnf )) were sequenced and expression differences were compared throughout gonadal regression and recrudescence using quantitative RT-PCR. Our results suggest that short days trigger expression of Hif1a, Serpine1, and Tgfbr3 to inhibit angiogenesis or promote apoptosis during testicular regression, and also trigger expression of Tnf to promote angiogenesis during testicular recrudescence.

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Extracellular domain of TGFβ type III receptor inhibits angiogenesis and tumor growth in human cancer cells

Cited by 76 publications

References 34 publications

TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma

TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma

Bone Sialoprotein Mediates the Tumor Cell–Targeted Prometastatic Activity of Transforming Growth Factor β in a Mouse Model of Breast Cancer

Photoperiod-induced differential expression of angiogenesis genes in testes of adult Peromyscus leucopus

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