TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma - PubMed (original) (raw)

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

Jieqiong Liu et al. Proc Natl Acad Sci U S A. 2012.

Abstract

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.

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Conflict of interest statement

Conflict of interest statement: R.K.J. received research grants from Dyax, MedImmune, and Roche; received consultant fees from Dyax, Enlight, Noxxon, and SynDevRx; owns equity in Enlight, SynDevRx, and XTuit; and serves on the Board of Directors of XTuit and Board of Trustees of H&Q Healthcare Investors and H&Q Life Sciences Investors. Y.B. received consultant fees from XTuit. No reagents or funding from these companies were used in these studies.

Figures

Fig. 1.

Fig. 1.

Blocking TGF-β signaling inhibits the growth and metastasis of orthotopic mammary carcinoma. (A) Primary tumor growth curves in mice bearing parental (n = 9), mock (n = 8), and sTβRII-transfected (n = 6) MDA-MB-231 cells. *P < 0.0001. (B) Representative BLI of inguinal (In-LN) and axillary (A-LN) lymph nodes (n = 4). Color scale: min, 27; max, 30308. (C and D) Primary tumor growth curves (C; n = 8) and lung metastasis quantification (D; n = 12) in mice bearing parental, mock, and sTβRII-transfected 4T1 cells. (C) *P < 0.0001. (D) *P < 0.005. (E Left and Center) Primary tumor growth curves of MDA-MB-231 (Left) and 4T1 (Center) tumors treated with control IgG (13C4) or anti-TGF-β antibody, 1D11 (n = 8). *P < 0.0001. (Right) Quantification of 4T1 tumor lung metastasis (n = 8). *P < 0.005.

Fig. 2.

Fig. 2.

Blocking TGF-β signaling increases tumor blood vessel pericyte coverage and perfusion. (A) Representative images and quantification of immunofluorescence double staining for endothelial cells (CD31) and pericytes (NG2) in frozen sections of 4T1 and 4T1–sTβRII tumors. Green, CD31+ staining; red, NG2+ staining; yellow, colocalization of red and green. (B) Representative images and quantification of perfused blood vessels (FITC–lectin) and immunofluorescence staining for endothelial cells (CD31) in frozen sections of 4T1 and 4T1–sTβRII tumors. Green, FITC–lectin-labeled perfused vessels; red, CD31+ staining in nonperfused vessels; yellow, CD31+ staining of perfused vessels. P < 0.001.

Fig. 3.

Fig. 3.

Blocking TGF-β signaling improves intratumoral distribution of doxorubicin in orthotopic mammary carcinoma models. (A and B) Representative images of doxorubicin intratumoral distribution in 4T1 (A) and 4T1–sTβRII (B) tumors. Green, FITC–lectin-labeled perfused vessels; red, fluorescent doxorubicin; blue, DAPI. (C) Quantification of the fraction of tumor area positive for doxorubicin (n = 12 sections, with 3 sections per tumor). *P < 0.001.

Fig. 4.

Fig. 4.

Blocking TGF-β signaling decreases collagen I content and improves Doxil tissue penetration. (A) Representative images and quantification of collagen I immunofluorescent staining in 4T1 and 4T1–sTβRII tumors. Red, collagen I staining; blue, DAPI (×20). (B) Representative images and quantification of Doxil intratumoral distribution in 4T1 and 4T1–sTβRII tumors. Green, FITC-lectin labeled perfused vessels; red, fluorescent doxorubicin; blue, DAPI (n = 12 sections, with 3 sections per tumor). *P < 0.001.

Fig. 5.

Fig. 5.

Blocking TGF-β signaling enhances Doxil efficacy in orthotopic mammary carcinoma models. (A and B) Primary tumor growth of 4T1 and 4T1–sTβRII tumors, with or without Doxil treatment (A) and 4T1 (B) and MDA-MB-231 (C) tumors treated with saline (control), Doxil alone (9 mg/kg, weekly), 1D11 alone (5 mg/kg, three times a week), or combined Doxil and 1D11 (n = 8 in all groups).

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