Transforming growth factor-β in cancer and metastasis

Jakowlew, Sonia B.

doi:10.1007/s10555-006-9006-2

Cited by 481 publications

(403 citation statements)

References 179 publications

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“…AGTR1 signaling has been shown to increase the proliferation of stromal and tumor cells and the transcription of inflammatory cytokines and chemokines that promote cancer cell migration and dissemination (49). The reduction in active TGF-β1 levels by RAAS antagonists could also reduce metastasis (50). Consequently, in addition to improving the delivery of antitumor agents, losartan may also inhibit tumor progression and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors

Diop-Frimpong

Chauhan

Krane

et al. 2011

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

614

559

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The dense collagen network in tumors significantly reduces the penetration and efficacy of nanotherapeutics. We tested whether losartan-a clinically approved angiotensin II receptor antagonist with noted antifibrotic activity-can enhance the penetration and efficacy of nanomedicine. We found that losartan inhibited collagen I production by carcinoma-associated fibroblasts isolated from breast cancer biopsies. Additionally, it led to a dose-dependent reduction in stromal collagen in desmoplastic models of human breast, pancreatic, and skin tumors in mice. Furthermore, losartan improved the distribution and therapeutic efficacy of intratumorally injected oncolytic herpes simplex viruses. Finally, it also enhanced the efficacy of i.v. injected pegylated liposomal doxorubicin (Doxil). Thus, losartan has the potential to enhance the efficacy of nanotherapeutics in patients with desmoplastic tumors. drug delivery | matrix modifier | thrombospondin-1 | transforming growth factor β | transport A lthough nanotherapeutics have offered new hope for cancer treatment, their clinical efficacy is modest (1-4). This is partly because their penetration is hindered, especially in fibrotic tumors, where the small interfibrillar spacing in the interstitium retards the movement of particles larger than 10 nm (5-8). Pegylated liposomal doxorubicin (Doxil), approved by the Food and Drug Administration, and oncolytic viruses, currently in multiple clinical trials, represent two nanotherapeutics whose size (∼100 nm) hinders their intratumoral distribution and therapeutic effectiveness (9). Matrix modifiers such as bacterial collagenase, relaxin, and matrix metalloproteinase-1 and -8 have been used to modify the collagen or proteoglycan network in tumors and have improved the efficacy of intratumorally (i.t.) injected oncolytic viruses (8,(10)(11)(12)(13). However, these agents may produce normal tissue toxicity (e.g., bacterial collagenase) or increase the risk of tumor progression (e.g., relaxin, matrix metalloproteinases).Losartan (14)-approved to control hypertension in patients -does not have many of these safety risks. Furthermore, in addition to its antihypertensive properties, losartan is also an antifibrotic agent that has been shown to reduce the incidence of cardiac and renal fibrosis (15, 16). The antifibrotic effects of losartan are caused, in part, by the suppression of active transforming growth factor-β1 (TGF-β1) levels via an angiotensin II type I receptor (AGTR1)-mediated down-regulation of TGF-β1 activators such as thrombospondin-1 (TSP-1) (15-19). Using a dose that has minimal effects on mean arterial blood pressure (MABP), we show that losartan reduces collagen I levels in four tumor models-a spontaneous mouse mammary carcinoma (FVB MMTV PyVT), an orthotopic pancreatic adenocarcinoma (L3.6pl), and s.c. implanted fibrosarcoma (HSTS26T) and melanoma (Mu89). Losartan also improves the intratumoral penetration of nanoparticles injected i.t. or i.v.Based on these results, we tested how losartan would affect the distributi...

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Section: Discussionmentioning

confidence: 99%

Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors

Diop-Frimpong

Chauhan

Krane

et al. 2011

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

614

559

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“…High levels of TGF-␤1 are produced by many types of tumors and are associated with poor prognosis in cancer patients (32). Large amounts of TGF-␤1 affect the proliferation and differentiation of cells as well as migration, invasion, angiogenesis, and immune surveillance (41). We first demonstrated that overexpression and stimulation of IL-27 inhibit the expression of TGF-␤1 (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…The functional alteration of TGF-␤1 is due to changes in the degree of tumor differentiation and sensitivity to TGF-␤1 (41). High levels of TGF-␤1 are produced by many types of tumors and are associated with poor prognosis in cancer patients (32).…”

Section: Discussionmentioning

confidence: 99%

IL-27 Directly Restrains Lung Tumorigenicity by Suppressing Cyclooxygenase-2-Mediated Activities

Leu

Sun

et al. 2009

The Journal of Immunology

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Gene transfer of IL-27 to tumor cells has been proven to inhibit tumor growth in vivo by antiproliferation, antiangiogenesis, and stimulation of immunoprotection. To investigate the nonimmune mechanism of IL-27 that suppresses lung cancer growth, we have established a single-chain IL-27-transduced murine Lewis lung carcinoma (LLC-1) cell line (LLC-1/scIL-27) to evaluate its tumorigenic potential in vivo. Mice inoculated with LLC/scIL-27 displayed retardation of tumor growth. Production of IL-12, IFN-γ, and cytotoxic T cell activity against LLC-1 was manifest in LLC/scIL-27-injected mice. Of note, LLC-1/scIL-27 exhibited decreased expression of cyclooxygenase-2 (COX-2) and PGE2. On the cellular level, the LLC/scIL-27 transfectants had reduced malignancy, including down-regulation of vimentin expression and reduction of cellular migration and invasion. The suppression of tumorigenesis by IL-27 on lung cancer cells was further confirmed by the treatment with rIL-27 on the murine LLC-1 and human non-small cell lung carcinoma (NSCLC) cell lines. PGE2-induced vimentin expression, movement, and invasiveness were also suppressed by the treatment with rIL-27. Our data show that IL-27 not only suppresses expression of COX-2 and PGE2 but also decreases the levels of vimentin and the abilities of cellular migration and invasion. Furthermore, inoculation of LLC/scIL-27 into immunodeficient NOD/SCID mice also exhibited reduced tumor growth. Our data indicate that IL-27-induced nonimmune responses can contribute to significant antitumor effects. Taken together, the results suggest that IL-27 may serve as an effective agent for lung cancer therapy in the future.

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“…This also appears to protect cancer cells from the toxic actions of chemotherapy and radiotherapy, rendering these treatment modalities less effective. Many epithelial tumor entities including gastric and cervical cancer as well as cancers of head, neck, breast and lung express high levels of EGF, TGF-β1 and TNF-α, which are associated with advanced disease and poor clinical prognosis (Stuelten et al, 2005;Jakowlew et al, 2006;Van et al, 2006;Bussink et al, 2008;Wu et al, 2009). Higher level expression of EGF, TGF-β1 and TNF-α have been inversely correlated to survival in these patients and high expression levels have been found in advanced tumor stages (Friess et al, 1999;Ghaneh et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Association Between EGF, TGF-β1 and TNF-α Gene Polymorphisms and Hepatocellular Carcinoma

Shi

Ren²,

Lu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Transforming growth factor-β in cancer and metastasis

Cited by 481 publications

References 179 publications

Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors

Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors

IL-27 Directly Restrains Lung Tumorigenicity by Suppressing Cyclooxygenase-2-Mediated Activities

Association Between EGF, TGF-β1 and TNF-α Gene Polymorphisms and Hepatocellular Carcinoma

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