Plasma levels of transforming growth factor‐1β and α2‐macroglobulin before and after radical prostatectomy: association to clinicopathological parameters

Sinnreich, O.; Kratzsch, Jürgen; Reichenbach, A.; Gläser, Christiane; Huse, Klaus; Birkenmeier, Gerd

doi:10.1002/pros.20062

Cited by 19 publications

(13 citation statements)

References 23 publications

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“…2A). To explore an alternative pathway other than neutralizing growth factors (21,22), we blocked the cellular receptor with a polyclonal Ab that presumably does not mediate clearance of growth factors. As depicted in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…At present, the beneficial impact of A2M* on tumors and other diseases have been mainly discussed in terms of clearing growth factors, especially TGF-β1 that is known to strongly promote the malignancy of gliomas (9,22,26). However, our experiments with polyclonal Abs may argue against this assumption because growth factors cannot be cleared by them.…”

Section: Discussionmentioning

confidence: 99%

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α2-Macroglobulin Inhibits the Malignant Properties of Astrocytoma Cells by Impeding β-Catenin Signaling

et al. 2010

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Targets that could improve the treatment of brain tumors remain important to define. This study of a transformation-associated isoform of α2-macroglobulin (A2M*) and its interaction with the low-density lipoprotein receptor-related protein-1 (LRP1) suggests a new mechanism for abrogating the malignant potential of astrocytoma cells. LRP1 bound A2M* found to be associated with an inhibition of tumor cell proliferation, migration, invasion, spheroid formation, and anchorage-independent growth. Transcriptional studies implicated effects on the Wnt/β-catenin signaling pathway. Notably, LRP1 antibodies could phenocopy the effects of A2M*. Our findings suggest a pathway of tumor suppression in astrocytoma that might be tractable to therapeutic exploitation. Cancer Res; 70(1); 277-87. ©2010 AACR.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

α2-Macroglobulin Inhibits the Malignant Properties of Astrocytoma Cells by Impeding β-Catenin Signaling

et al. 2010

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“…In patients with prostate cancer, α-2-macroglobulin is proteolytically activated and signals predominantly through GRP78 to promote the proliferation and survival of cancer cells (36,37). The levels of both native and activated α-2-macroglobulin in serum decrease during disease progression (38). Our observations suggest that prostatic cancer cells readily take up α-2-macroglobulin from serum, because the phage with the insert PKRGFQD most likely binds to the α-2-macroglobulin present in the circulation before internalization of the whole complex by the cells.…”

Section: Discussionmentioning

confidence: 99%

“…Affinity purification identified proteins that are all associated with cancer progression. In particular, α-2-macroglobulin and GRP78 are clearly implicated in the development of metastatic prostate cancer (35,38,48,56,58,59). We previously targeted prostate cancer with phage that bind to GRP78 (15).…”

Section: Discussionmentioning

confidence: 99%

Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors

Mandelin

Cardó-Vila

Driessen

et al. 2015

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

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We performed combinatorial peptide library screening in vivo on a novel human prostate cancer xenograft that is androgenindependent and induces a robust osteoblastic reaction in bonelike matrix and soft tissue. We found two peptides, PKRGFQD and SNTRVAP, which were enriched in the tumors, targeted the cell surface of androgen-independent prostate cancer cells in vitro, and homed to androgen receptor-null prostate cancer in vivo. Purification of tumor homogenates by affinity chromatography on these peptides and subsequent mass spectrometry revealed a receptor for the peptide PKRGFQD, α-2-macroglobulin, and for SNTRVAP, 78-kDa glucose-regulated protein (GRP78). These results indicate that GRP78 and α-2-macroglobulin are highly active in osteoblastic, androgen-independent prostate cancer in vivo. These previously unidentified ligand-receptor systems should be considered for targeted drug development against human metastatic androgen-independent prostate cancer.peptides | ligand receptors | phage display | GRP78 | tumor targeting A ndrogen deprivation remains the standard therapy for metastatic prostate cancer. Despite the favorable initial response, in most cases the disease progresses, becomes androgen-independent, and gives rise to soft tissue and osteoblastic bone metastases that ultimately lead to death (1, 2). Paradoxically, all currently available animal models of osteoblastic bone metastases are androgen dependent (3-6). The first (to our knowledge) human prostate cancer xenograft model that does not express androgen receptor but still induces a strong osteogenic response led Li et al. (7) to conclude that androgen receptor-null cells contribute to the castrate-resistant osteoblastic progression of prostate cancer and that targeting these cells will be critical in the treatment of prostate cancer bone metastases.In vivo phage display can be used to explore the surface of cells in their anatomical microenvironment (8)(9)(10)(11)(12)(13)(14). This technology enables the identification of molecular signatures that could allow targeted systemic delivery of therapeutic agents to cancer tissues (9,12,15,16). Using such methodology and the special prostate cancer model (7), we hypothesized that ligandreceptor pairs for targeting metastasizing androgen-independent prostate cancer cells could be identified.Here we select two novel ligand peptides that were selected in vivo from human androgen-independent prostate cancer xenografts. We show that they target the surface of an androgenindependent prostatic cell line in vitro and home to androgen receptor-null prostate tumors in vivo. With affinity chromatography, we next isolated their respective receptors, 78-kDa glucose-regulated protein (GRP78) and α-2-macroglobulin, from tumor lysates and as a proof of principle verified the peptide-GRP78 interaction in vitro with recombinant GRP78. These data confirm that GRP78 is a functional molecular target on prostatic cancer cell surfaces in vivo. Such ligand-receptor systems may be applicable to targeted therapy and should be...

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“…Active TGF-β produced by tumor and stroma contributes to breast cancer progression and metastatic potential through autocrine and paracrine eff ects (52). TGF-β plasma levels are also elevated in prostate cancer patients, and correlate with advanced stage, metastases and poorer clinical outcome (53)(54)(55)(56). Increased TGF-β expression is observed in tumor cells and stroma (57)(58)(59).…”

Section: Rationale For Tgf-b Antagonist Therapy For Cancer Patientsmentioning

confidence: 99%

TGF Blockade as Anticancer Therapy

Teicher¹,

Yingling²,

McPherson³

2008

AACR Education book

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Plasma levels of transforming growth factor‐1β and α2‐macroglobulin before and after radical prostatectomy: association to clinicopathological parameters

Cited by 19 publications

References 23 publications

α2-Macroglobulin Inhibits the Malignant Properties of Astrocytoma Cells by Impeding β-Catenin Signaling

α2-Macroglobulin Inhibits the Malignant Properties of Astrocytoma Cells by Impeding β-Catenin Signaling

Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors

TGF Blockade as Anticancer Therapy

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