Systemic administration of a soluble betaglycan suppresses tumor growth, angiogenesis, and matrix metalloproteinase-9 expression in a human xenograft model of prostate cancer

Bandyopadhyay, Abhik; Wang, Long; López‐Casillas, Fernando; Mendoza, Valentín; Yeh, I‐Tien; Sun, LuZhe

doi:10.1002/pros.20166

Cited by 62 publications

(59 citation statements)

References 29 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.

288

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.

288

234

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“…S2). Similarly, soluble betaglycan has recently been shown to decrease MMP-9 levels in a prostate cancer model and reduce breast cancer cell migration and invasion (20,39). Thus, in ovarian cancer progression, betaglycan may carry out a dual role; first by directly facilitating the tumor suppressor Figure 6.…”

Section: Discussionmentioning

confidence: 99%

Loss of Betaglycan Expression in Ovarian Cancer: Role in Motility and Invasion

et al. 2007

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The transforming growth factor-B (TGF-B) superfamily members, TGF-B, activin, and inhibin, all have prominent roles in regulating normal ovarian function. Betaglycan, or the type III TGF-B receptor, is a coreceptor that regulates TGF-B, activin, and inhibin signaling. Here, we show that betaglycan expression is frequently decreased or lost in epithelial derived ovarian cancer at both the mRNA and protein level, with the degree of loss correlating with tumor grade. Treatment of ovarian cancer cell lines with the methyltransferase inhibitor 5-aza-2-deoxycytidine and the histone deacetylase inhibitor trichostatin A resulted in significant synergistic induction of betaglycan message levels and increased betaglycan protein expression, indicating that epigenetic silencing may play a role in the loss of betaglycan expression observed in ovarian cancer. Although restoring betaglycan expression in Ovca429 ovarian cancer cells is not sufficient to restore TGF-B-mediated inhibition of proliferation, betaglycan significantly inhibits ovarian cancer cell motility and invasiveness. Furthermore, betaglycan specifically enhances the antimigratory effects of inhibin and the ability of inhibin to repress matrix metalloproteinase levels in these cells. These results show, for the first time, epigenetic regulation of betaglycan expression in ovarian cancer, and a novel role for betaglycan in regulating ovarian cancer motility and invasiveness. [Cancer Res 2007;67(11):5231-8]

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“…animal models (18,21,22). However, whether the blockade of TGFh signaling in the epithelium or stroma is responsible for the antitumor actions of the inhibitors remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

“…Human prostate stromal cells (PrSC) were purchased from Cambrex and the human prostate carcinoma cell line DU145 was originally purchased from the American Type Culture Collection. These cells were maintained in McCoy's medium supplemented with L-serine, L-asparagine, L-glutamine, sodium pyruvate, MEM nonessential amino acids, MEM amino acids without L-glutamine, MEM vitamins, penicillin, streptomycin, gentamicin, sodium bicarbonate, and 10% FBS, as previously described (21). Cells were maintained at 37jC in a 5% CO 2 humidified incubator.…”

Section: Methodsmentioning

confidence: 99%

Transforming Growth Factor-β Signaling in Prostate Stromal Cells Supports Prostate Carcinoma Growth by Up-regulating Stromal Genes Related to Tissue Remodeling

Verona¹,

Elkahloun

Yang³

et al. 2007

Cancer Research

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Increasing evidence points to an active stromal involvement in cancer initiation and progression. Cytokines derived from tumor cells are believed to modulate stromal cells to produce growth and angiogenic factors, which in turn provide the tumor with the necessary microenvironment for expansion and invasion. Transforming growth factor B (TGFB) has been implicated as a candidate cytokine to mediate this communication. However, how its signaling in stromal cells regulates tumorigenesis and tumor progression remains unresolved. We show that normal, presenescent fibroblasts or prostate stromal cells cotransplanted with prostate carcinoma cells s.c. into nude mice reduced tumor latency and accelerated tumor growth. When their TGFB signaling was blocked, the fibroblasts and stromal cells still stimulated tumor initiation but no longer supported tumor growth as control cells did. The loss of the tumor growth-promoting activity of the stromal cells with attenuated TGFB signaling was not associated with altered cellular senescence or tumor angiogenicity. TGFB and the medium conditioned by the prostate carcinoma cells stimulated myofibroblast differentiation of the intact stromal cells, but not the stromal cells with attenuated TGFB signaling. Gene microarray and quantitative reverse transcription-PCR analyses showed that TGFB upregulated a host of genes in stromal cells that are involved in tissue remodeling and wound healing. Thus, our study provides evidence for TGFB as a supporting agent in tumor progression through the induction of a perpetual wound healing process in the tumor microenvironment. [Cancer Res 2007;67(12):5737-46]

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Systemic administration of a soluble betaglycan suppresses tumor growth, angiogenesis, and matrix metalloproteinase-9 expression in a human xenograft model of prostate cancer

Abstract: Our results for the first time indicate that TGFbeta blockade by systemic sBG administration can inhibit DU145 prostate xenograft growth and angiogenesis. The inhibition is likely in part mediated by the attenuation of TGFbeta-induced MMP-9 expression.

Cited by 62 publications

References 29 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

Loss of Betaglycan Expression in Ovarian Cancer: Role in Motility and Invasion

Transforming Growth Factor-β Signaling in Prostate Stromal Cells Supports Prostate Carcinoma Growth by Up-regulating Stromal Genes Related to Tissue Remodeling

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