The Tumor Microenvironments of Lethal Prostate Cancer

Harryman, William L.; Warfel, Noel A.; Nagle, Raymond B.; Cress, Anne E.

doi:10.1007/978-3-030-32656-2_8

Cited by 9 publications

(10 citation statements)

References 169 publications

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“…Current mechanistic concepts for this PCa transition to aggressive, metastatic CRPC have highlighted the involvement of a hypoxic tumor environment, inflamed peri-prostatic adipose tissues, and inflammatory signaling pathways that activate androgen receptors and promote PCa progression. It is well known that the hypoxic tumor microenvironment results in hypoxia-induced transcription factors (HIF-1α, HIF-2α)-mediated production of locally produced chemokines/cytokines [26][27][28][29][30] emanating from normal prostate epithelial cells, periprostatic adipocytes, and PCa cells. Thus, a novel therapy that targets inflammatory signaling pathways may represent a potent mechanism to prevent PCa progression and to reduce PCa lethality.…”

Section: Discussionmentioning

confidence: 99%

A Humanized Monoclonal Antibody Targeting Extracellular Nicotinamide Phosphoribosyltransferase Prevents Aggressive Prostate Cancer Progression

et al. 2021

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Prostate cancer (PCa) is the major cause of cancer-related death in males; however, effective treatments to prevent aggressive progression remain an unmet need. We have previously demonstrated that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator that promotes PCa invasion. In the current study, we further investigate the therapeutic effects of an eNAMPT-neutralizing humanized monoclonal antibody (ALT-100 mAb) in preclinical PCa orthotopic xenograft models. We utilized human aggressive PCa cells (DU145 or PC3) for prostate implantation in SCID mice receiving weekly intraperitoneal injections of either ALT-100 mAb or IgG/PBS (control) for 12 weeks. Prostatic tumors and solid organs were examined for tumor growth, invasion, and metastasis and for biochemical and immunohistochemistry evidence of NFκB activation. ALT-100 mAb treatment significantly improved overall survival of SCID mice implanted with human PCa orthotopic prostate xenografts while inducing tumor necrosis, decreasing PCa proliferation and reducing local invasion and distal metastases. The ALT-100 mAb inhibits NFκB phosphorylation and signaling in PCa cells both in vitro and in vivo. This study demonstrates that eNAMPT neutralization effectively prevents human PCa aggressive progression in preclinical models, indicating its high potential to directly address the unmet need for an effective targeted therapy for patients with aggressive PCa.

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Section: Discussionmentioning

confidence: 99%

A Humanized Monoclonal Antibody Targeting Extracellular Nicotinamide Phosphoribosyltransferase Prevents Aggressive Prostate Cancer Progression

et al. 2021

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“…Taken together, the studies indicate that aberrant E-cadherin levels, distribution, and perhaps function occurs during tumor progression. Dissemination through the lymph nodes or through the vascular system are different microenvironments where tumors utilize a cohesive adhesion phenotype (reviewed in Harryman et al (2019) , Harryman et al (2021) .…”

Section: Cell-cell (E-cadherin Cdh1) and Cell-ecm (α6 Integrin Cd49f)...mentioning

confidence: 99%

“…Early work recognized the importance of reciprocal interactions of the tumor and muscle that coordinatively resulted in organ escape ( Ayala et al, 2003 ). While matrix metalloproteinases (MMPs) and corresponding ECM changes occur during prostate cancer progression ( Harryman et al, 2019 ), it is unknown how the muscle and tumor alterations cooperate. Recent work has centered on the view that the plasticity of cell phenotypes in both compartments may be responsive to growth factors and secreted proteins as agents of change.…”

Section: The Growth Factors That Influence Tumor Integrin Function In...mentioning

confidence: 99%

“…We propose that the heterogeneity of cell-cell and cell-ECM adhesion receptors is an important driver of aggressive tumor networks and has functional consequences in cases of muscle invasive and lethal carcinomas. The heterogeneity is functional in that it provides a biophysical advantage for invasion of tumor networks through the tensile muscle and survival of the tumor network during progression ( Harryman et al, 2019 ). Genomic heterogeneity also arises in human prostate tumors within the muscle rich organ as multiple spatially intermixed lineages that persist within distant lesions ( Woodcock et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers

Harryman

Marr

Nagle

et al. 2022

Front. Cell Dev. Biol.

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Muscle-invasive lethal carcinomas traverse into and through this specialized biophysical and growth factor enriched microenvironment. We will highlight cancers that originate in organs surrounded by smooth muscle, which presents a barrier to dissemination, including prostate, bladder, esophageal, gastric, and colorectal cancers. We propose that the heterogeneity of cell-cell and cell-ECM adhesion receptors is an important driver of aggressive tumor networks with functional consequences for progression. Phenotype heterogeneity of the tumor provides a biophysical advantage for tumor network invasion through the tensile muscle and survival of the tumor network. We hypothesize that a functional epithelial-mesenchymal cooperation (EMC)exists within the tumor invasive network to facilitate tumor escape from the primary organ, invasion and traversing of muscle, and navigation to metastatic sites. Cooperation between specific epithelial cells within the tumor and stromal (mesenchymal) cells interacting with the tumor is illustrated using the examples of laminin-binding adhesion molecules—especially integrins—and their response to growth and inflammatory factors in the tumor microenvironment. The cooperation between cell-cell (E-cadherin, CDH1) and cell-ECM (α6 integrin, CD49f) expression and growth factor receptors is highlighted within poorly differentiated human tumors associated with aggressive disease. Cancer-associated fibroblasts are examined for their role in the tumor microenvironment in generating and organizing various growth factors. Cellular structural proteins are potential utility markers for future spatial profiling studies. We also examine the special characteristics of the smooth muscle microenvironment and how invasion by a primary tumor can alter this environment and contribute to tumor escape via cooperation between epithelial and stromal cells. This cooperative state allows the heterogenous tumor clusters to be shaped by various growth factors, co-opt or evade immune system response, adapt from hypoxic to normoxic conditions, adjust to varying energy sources, and survive radiation and chemotherapeutic interventions. Understanding the epithelial-mesenchymal cooperation in early tumor invasive networks holds potential for both identifying early biomarkers of the aggressive transition and identification of novel agents to prevent the epithelial-mesenchymal cooperation phenotype. Epithelial-mesenchymal cooperation is likely to unveil new tumor subtypes to aid in selection of appropriate therapeutic strategies.

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“…MM and metastatic prostate cancer progression involves bone marrow disease in 100% and 92% of patients, respectively. [5][6][7][8][9] Herein, we describe the synthesis of cyclized…”

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confidence: 99%

Bioactivity improvement via display of the hydrophobic core of HYD1 in a cyclic β‐hairpin‐like scaffold, MTI‐101

et al. 2020

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HYD1 is an all D-amino acid linear 10-mer peptide that was discovered by one-beadone-compound screening. HYD1 has five hydrophobic amino acids flanked by polar amino acids. Alanine scanning studies showed that alternating hydrophobic amino acid residues and N-and C-terminal lysine side chains were contributors to the biological activity of the linear 10-mer analogs. This observation led us to hypothesize that display of the hydrophobic pentapeptide sequence of HYD1 in a cyclic betahairpin-like scaffold could lead to better bioavailability and biological activity. An amphipathic pentapeptide sequence was used to form an antiparallel strand and those strands were linked via dipeptide-like sequences selected to promote β-turns.Early cyclic analogs were more active but otherwise mimicked the biological activity of the linear HYD1 peptide. The cyclic peptidomimetics were synthesized using standard Fmoc solid phase synthesis to form linear peptides, followed by solution phase or on-resin cyclization. SAR studies were carried out with an aim to increase the potency of these drug candidates for the killing of multiple myeloma cells in vitro.The solution structures of 1, 5, and 10 were elucidated using NMR spectroscopy. 1 H NMR and 2D TOCSY studies of these peptides revealed a downfield H α proton chemical shift and 2D NOE spectral analysis consistent with a β-hairpin-like structure. | INTRODUCTIONMultiple myeloma (MM) develops solid tumors in the bone marrow microenvironment due to interactions with cell adhesion receptors involved in cell-cell and cell-extracellular matrix interactions. MM tumors thrive in the bone marrow microenvironment due to access to growth factors that are secreted from neighboring stromal cells that normally nurture developing hematopoietic cells. [1][2][3][4] Bone marrow metastasis is common for many solid tumors such as prostate, lung, and breast. MM and metastatic prostate cancer progression involves bone marrow disease in 100% and 92% of patients, respectively. [5][6][7][8][9] Herein, we describe the synthesis of cyclized

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The Tumor Microenvironments of Lethal Prostate Cancer

Cited by 9 publications

References 169 publications

A Humanized Monoclonal Antibody Targeting Extracellular Nicotinamide Phosphoribosyltransferase Prevents Aggressive Prostate Cancer Progression

A Humanized Monoclonal Antibody Targeting Extracellular Nicotinamide Phosphoribosyltransferase Prevents Aggressive Prostate Cancer Progression

Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers

Bioactivity improvement via display of the hydrophobic core of HYD1 in a cyclic β‐hairpin‐like scaffold, MTI‐101

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