Impact of the non‐cellular tumor microenvironment on metastasis: Potential therapeutic and imaging opportunities

Cretu, Alexandra; Brooks, Peter C.

doi:10.1002/jcp.21222

Cited by 58 publications

(48 citation statements)

References 117 publications

(246 reference statements)

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“…Matrix adhesion and modulation is an important factor in tumor progression (33,34) and CD44 has been suggested to contribute to tumor progression via hyaluronan binding (10). Because apoptosis resistance of ASML wt cells is supported by the tumor matrix, we proceeded to explore the matrix secreted by ASML wt in comparison with the ASML-CD44v kd cells.…”

Section: Asml Wt But Not Asml-cd44v Kd Cells Generate An Adhesive Matrixmentioning

confidence: 99%

CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance

Klingbeil

Marhaba

Jung

et al. 2009

Molecular Cancer Research

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CD44 designates a large family of proteins with a considerable structural and functional diversity, which are generated from one gene by alternative splicing. As such, the overexpression of CD44 variant isoform (CD44v) has been causally related to the metastatic spread of cancer cells. To study the underlying mechanism, stable knockdown clones with deletion of exon v7 containing CD44 isoforms (CD44v kd ) of the highly metastatic rat adenocarcinoma line BSp73ASML (ASML wt ) were established. ASML-CD44v kd clones hardly form lung metastases after intrafootpad application and the metastatic load in lymph nodes is significantly reduced. Rescuing, albeit at a reduced level, CD44v expression in ASML-CD44v kd cells (ASML-CD44v rsc ) restores the metastatic potential. The following major differences in ASML wt , ASML-CD44v kd , and ASML-CD44v rsc clones were observed: (a) ASML wt cells produce and assemble a matrix in a CD44v-dependent manner, which supports integrin-mediated adhesion and favors survival. This feature is lost in the ASML-CD44v kd cells. (b) CD44v cross-linking initiates phosphatidylinositol 3-kinase/Akt activation in ASML wt cells. Accordingly, apoptosis resistance is strikingly reduced in ASML-CD44v kd cells. The capacity to generate an adhesive matrix but not apoptosis resistance is restored in ASML-CD44v rsc cells. These data argue for a 2-fold effect of CD44v on metastasis formation: CD44v-mediated matrix formation is crucial for the settlement and growth at a secondary site, whereas apoptosis resistance supports the efficacy of metastasis formation.

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Section: Asml Wt But Not Asml-cd44v Kd Cells Generate An Adhesive Matrixmentioning

confidence: 99%

CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance

Klingbeil

Marhaba

Jung

et al. 2009

Molecular Cancer Research

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“…Pancreatic diseases such as pancreatic cancer and chronic pancreatitis are characterized by profound alterations of ECM formation and composition. 16 In fact, extensive remodeling of the ECM adjacent to parenchymal abnormalities is closely associated with tumor development and progression, 29,30 which are likely to be reflected in the 3D architecture as observed by MRI. ECM thickness, which may reflect its protein composition and its ability to tolerate mechanical stress, 31 can be measured in volume-rendered MRI images.…”

Section: Organization Of the Ecm In The Pancreasmentioning

confidence: 99%

Visualization of Mouse Pancreas Architecture Using MR Microscopy

Grippo

Venkatasubramanian

Knop

et al. 2011

The American Journal of Pathology

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Pancreatic diseases, which include diabetes, pancreatitis, and pancreatic cancer, are often difficult to detect and/or stage, contributing to a reduced quality of life and lifespan for patients. Thus, there is need for a technology that can visualize tissue changes in the pancreas, improve understanding of disease progression, and facilitate earlier detection in the human population. Because of low spatial resolution, current clinical magnetic resonance imaging (MRI) at low field strength has yet to fully visualize the exocrine, endocrine, vascular, and stromal components of the pancreas. We used high field strength magnetic resonance microscopy ( MRI) to image mouse pancreas ex vivo without contrast agents at high spatial resolution. We analyzed the resulting high-resolution images using volume rendering to resolve components in the pancreas, including acini, islets, blood vessels, and extracellular matrix. Locations and dimensions of pancreatic components as seen in three-dimensional MRI were compared with histological images, and good correspondence was found. Future longitudinal studies could expand on the use of in vivo MRI in mouse models of pancreatic diseases. Capturing three-dimensional structural changes through MRI could help to identify early cellular and tissue changes associated with pancreatic disease, serving as a mode of improved detection in the clinic for endocrine and exocrine pathologies.

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“…The transmission of signals between the ECM and neighboring cells occurs mainly through the integrins. These proteins have the capability to transduce mechanical cues created by the ECM or the cell cytoskeleton into chemical signals that regulate many cellular processes such as proliferation, survival, migration, and invasion [80,82,84,89,90]. …”

Section: The Extracellular Matrix (Ecm) and Regulation Of Invasion Anmentioning

confidence: 99%

“…The ECM consists of proteins that possess multiple functions and that provide vital signals for tumor progression and metastatic spread [79][80][81][82][83][84][85]. The matrix metalloproteinases (MMPs) with their proteolytic activity are key modulators of the TME and the most prominent family of proteases associated with tumorigenesis.…”

Section: The Extracellular Matrix (Ecm) and Regulation Of Invasion Anmentioning

confidence: 99%

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

Schwendener¹,

Mete²

2013

Frontiers in Clinical Drug Research - Anti-Cancer Agents

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Solid tumors grow within a complex microenvironment composed of diverse cell types such as fibroblasts, endothelial cells, mast cells, macrophages and immune cells that are attracted by tumor cell derived factors and embedded in an extracellular matrix. Molecular and cellular interactions between epithelial cells and cells surrounding the tumor stroma promote growth, invasion and spread of tumors. To delay or impede tumor growth, the tumor microenvironment (TME) is increasingly being explored as a potential therapeutic target for which novel strategies are developed. lt;/pgt;lt;pgt; This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed. This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed.

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Impact of the non‐cellular tumor microenvironment on metastasis: Potential therapeutic and imaging opportunities

Cited by 58 publications

References 117 publications

CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance

CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance

Visualization of Mouse Pancreas Architecture Using MR Microscopy

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

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