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22 pages, 526 KiB

Open AccessArticle

Tumor-Promoting Circuits That Regulate a Cancer-Related Chemokine Cluster: Dominance of Inflammatory Mediators Over Oncogenic Alterations

by Tal Leibovich-Rivkin, Yosef Buganim, Hilla Solomon, Tsipi Meshel, Varda Rotter and Adit Ben-Baruch

Cancers 2012, 4(1), 55-76; https://doi.org/10.3390/cancers4010055 - 20 Jan 2012

Cited by 3 | Viewed by 7414

Abstract

Here, we investigated the relative contribution of genetic/signaling components versus microenvironmental factors to the malignancy phenotype. In this system, we took advantage of non-transformed fibroblasts that carried defined oncogenic modifications in Ras and/or p53. These cells were exposed to microenvironmental pressures, and the expression of a cancer-related chemokine cluster was used as readout for the malignancy potential (CCL2, CCL5, CXCL8, CXCL10). In cells kept in-culture, synergism between Ras hyper-activation and p53 dysfunction was required to up-regulate the expression of the chemokine cluster. The in vivo passage of Ras^High/p53^Low-modified cells has led to tumor formation, accompanied by potentiation of chemokine release, implicating a powerful role for the tumor microenvironment in up-regulating the chemokine cluster. Indeed, we found that inflammatory mediators which are prevalent in tumor sites, such as TNFa and IL-1β, had a predominant impact on the release of the chemokines, which was substantially higher than that obtained by the oncogenic modifications alone, possibly acting through the transcription factors AP-1 and NF-kB. Together, our results propose that in the unbiased model system that we were using, inflammatory mediators of the tumor milieu have dominating roles over oncogenic modifications in dictating the expression of a pro-malignancy chemokine readout. Full article

(This article belongs to the Special Issue Tumor Cell Genesis and Its Microenvironment: Chicken or the Egg)

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10 pages, 634 KiB

Open AccessArticle

Tertiary Intratumor Lymphoid Tissue in Colo-Rectal Cancer

by Francesca Bergomas, Fabio Grizzi, Andrea Doni, Samantha Pesce, Luigi Laghi, Paola Allavena, Alberto Mantovani and Federica Marchesi

Cancers 2012, 4(1), 1-10; https://doi.org/10.3390/cancers4010001 - 28 Dec 2011

Cited by 86 | Viewed by 13541

Abstract

Ectopic (or tertiary) lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21⁺ follicular dendritic cells (FDC). We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS). B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV). Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response. Full article

(This article belongs to the Special Issue Tumor Cell Genesis and Its Microenvironment: Chicken or the Egg)

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Review

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26 pages, 885 KiB

Open AccessReview

Tumor Microenvironment in the Brain

by Mihaela Lorger

Cancers 2012, 4(1), 218-243; https://doi.org/10.3390/cancers4010218 - 22 Feb 2012

Cited by 88 | Viewed by 10931

Abstract

In addition to malignant cancer cells, tumors contain a variety of different stromal cells that constitute the tumor microenvironment. Some of these cell types provide crucial support for tumor growth, while others have been suggested to actually inhibit tumor progression. The composition of tumor microenvironment varies depending on the tumor site. The brain in particular consists of numerous specialized cell types such as microglia, astrocytes, and brain endothelial cells. In addition to these brain-resident cells, primary and metastatic brain tumors have also been shown to be infiltrated by different populations of bone marrow-derived cells. The role of different cell types that constitute tumor microenvironment in the progression of brain malignancies is only poorly understood. Tumor microenvironment has been shown to be a promising therapeutic target and diagnostic marker in extracranial malignancies. A better understanding of tumor microenvironment in the brain would therefore be expected to contribute to the development of improved therapies for brain tumors that are urgently required due to a poor availability of treatments for these malignancies. This review summarizes some of the known interactions between brain tumors and different stromal cells, and also discusses potential therapeutic approaches within this context. Full article

(This article belongs to the Special Issue Tumor Cell Genesis and Its Microenvironment: Chicken or the Egg)

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12 pages, 106 KiB

Open AccessReview

Actin—Towards a Deeper Understanding of the Relationship Between Tissue Context, Cellular Function and Tumorigenesis

by Virginia A. Spencer

Cancers 2011, 3(4), 4269-4280; https://doi.org/10.3390/cancers3044269 - 14 Dec 2011

Cited by 8 | Viewed by 6467

Abstract

It is well-established that the actin cytoskeleton plays an important role in tumor development yet the contribution made by nuclear actin is ill-defined. In a recent study, nuclear actin was identified as a key mediator through which laminin type III (LN1) acts to control epithelial cell growth. In the breast, epithelial tumors are surrounded by an environment which lacks LN1. These findings point to actin as a potential mediator of tumor development. Here our current understanding of the roles of cytoplasmic and nuclear actin in normal and tumor cell growth is reviewed, relating these functions to cell phenotype in a tissue context. Full article

(This article belongs to the Special Issue Tumor Cell Genesis and Its Microenvironment: Chicken or the Egg)

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