Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival

Cieslewicz, Maryelise; Tang, Jingjing; Yu, Jonathan L.; Cao, Hua; Zavaljevski, Maja; Motoyama, Koka; Lieber, André; Raines, Elaine W.; Pun, Suzie H.

doi:10.1073/pnas.1312197110

Cited by 265 publications

(240 citation statements)

References 35 publications

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“…In recent years, many reports showed that TAMs are strongly associated with advanced tumor stage and poor progress in several types of cancer (12,14,46). Consequently, therapeutic targeting of TAMs has been proposed for cancer therapy to delay tumor growth (20)(21)(22)25). Mannose receptor is a pathogen recognition receptor and the major receptor responsible for endocytosis in dendritic cells (47).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, TAMs have been investigated as novel therapeutic targets of cancer therapy (20)(21)(22)(23)(24). However, the therapies being trialed kill not only TAMs in cancer stroma, but also other M2 macrophages throughout the body that are important for normal processes including parasite containment, promotion of tissue remodeling, and immune regulation.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Photodynamic Therapy Targeting Cancer Cells and Tumor-Associated Macrophages

Hayashi,

Kataoka,

Yano

et al. 2015

Molecular Cancer Therapeutics

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Tumor-associated macrophages (TAM) in cancer stroma play important roles for cancer cell growth, invasion, angiogenesis, and metastases. We synthesized a novel photosensitizer, mannose-conjugated chlorin (M-chlorin), designed to bind mannose receptors highly expressed on TAMs. We evaluated the newly available photodynamic therapy (PDT) with M-chlorin against gastric and colon cancer. We evaluated PDT with Mchlorin for in vitro cytotoxicity and apoptosis induction in cancer cells compared with chlorin alone and glucose-conjugated chlorin (G-chlorin). The subcellular localization of Mchlorin was observed by confocal microscopy, and the Mchlorin PDT effects against TAMs including THP-1-induced M2-polarized macrophages were evaluated. Anticancer effects were also investigated in an allograft model where cytotoxic effects against TAMs in the cancer cell stroma were analyzed by immunohistochemistry. M-chlorin PDT strongly induced cell death in cancer cells to almost the same extent as G-chlorin PDT by inducing apoptosis. M-chlorin was incorporated into cancer cells where it localized mainly in lysosomes and endoplasmic reticula. M-chlorin PDT revealed strong cytotoxicity for M2 macrophages induced from THP-1 cell lines, and it induced stronger cytotoxicity than G-chlorin PDT in the allograft model through killing both cancer cells and TAMs in the cancer stroma. The M-chlorin PDT produced strong cytotoxicity against cancer tissue by inducing apoptosis of both cancer cells and TAMs in the cancer stroma. This novel PDT thus stands as a new candidate for very effective, next-generation PDT. Mol Cancer Ther; 14(2); 452-60. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel Photodynamic Therapy Targeting Cancer Cells and Tumor-Associated Macrophages

Hayashi,

Kataoka,

Yano

et al. 2015

Molecular Cancer Therapeutics

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“…Therefore, they have been explored for use as targeting tools in drug delivery, either fused to therapeutic proteins [5], coupled to drugs or therapeutic nucleic acids [2,17], or as functionalizing agents of different types of nanoparticles intended as drug carriers [1,8]. Under the combined development of materials sciences and nanomedicine it is however unclear whether tumor-homing peptides are more effective in promoting passenger drug penetration when formulated as plain molecular preparations or as multimeric presentations on nanoparticulate entities.…”

Section: Introductionmentioning

confidence: 99%

Formulating tumor-homing peptides as regular nanoparticles enhances receptor-mediated cell penetrability

Unzueta

Roldán

et al. 2015

Materials Letters

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Abstract:Homing peptides are exploited in nanomedicine to functionalize either free drugs or nanostructured materials used as drug carriers. However, the influence of multivalent versus monovalent peptide presentation on the interaction with the receptor and on the consequent intracellular delivery of the associated cargo remains poorly explored. By using a tumor-homing peptide (T22) with regulatable selfassembling properties we have investigated here if its display in a either a monomeric form or as multimeric, self-assembled protein nanoparticles might determine the efficacy of receptor-mediated penetrability into target cells. This has been monitored by using a fluorescent cargo protein (iRFP), which when fused to the homing peptide acts as convenient reporter. The results indicate that the nanoparticulate protein versions are significantly more efficient in mediating receptor-dependent uptake than their unassembled counterparts. These finding stresses an additional benefit of nanostructured materials based on repetitive building blocks, regarding the multivalent presentation of cell ligands that facilitate cell penetration in drug delivery applications.

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“…TAMs suppress antitumor immune responses, promote tumor invasion and angiogenesis, and are negatively associated with clinical outcomes (5). Macrophage depletion slows tumor progression in multiple cancer models (6)(7)(8). Dendritic cells (DCs) within tumor microenvironments also have aberrant phenotypes and have been implicated in suppression of antitumor adaptive immune responses (9).…”

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confidence: 99%

Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation

Triplett

Cardenas

Lancaster

et al. 2016

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

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Primary T-cell acute lymphoblastic leukemia (T-ALL) cells require stromal-derived signals to survive. Although many studies have identified cell-intrinsic alterations in signaling pathways that promote T-ALL growth, the identity of endogenous stromal cells and their associated signals in the tumor microenvironment that support T-ALL remains unknown. By examining the thymic tumor microenvironments in multiple murine T-ALL models and primary patient samples, we discovered the emergence of prominent epithelial-free regions, enriched for proliferating tumor cells and dendritic cells (DCs). Systematic evaluation of the functional capacity of tumor-associated stromal cells revealed that myeloid cells, primarily DCs, are necessary and sufficient to support T-ALL survival ex vivo. DCs support T-ALL growth both in primary thymic tumors and at secondary tumor sites. To identify a molecular mechanism by which DCs support T-ALL growth, we first performed gene expression profiling, which revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) and insulin-like growth factor I receptor (Igf1r) on T-ALL cells, with concomitant expression of their ligands by tumor-associated DCs. Both Pdgfrb and Igf1r were activated in ex vivo T-ALL cells, and coculture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DC-mediated T-ALL survival. Collectively, these studies provide the first evidence that endogenous tumor-associated DCs supply signals driving T-ALL growth, and implicate tumor-associated DCs and their mitogenic signals as auspicious therapeutic targets.

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Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival

Cited by 265 publications

References 35 publications

A Novel Photodynamic Therapy Targeting Cancer Cells and Tumor-Associated Macrophages

A Novel Photodynamic Therapy Targeting Cancer Cells and Tumor-Associated Macrophages

Formulating tumor-homing peptides as regular nanoparticles enhances receptor-mediated cell penetrability

Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation

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