Antitumor Activity and Bystander Effect of Adenovirally Delivered Tissue Inhibitor of Metalloproteinases-3

This study used a unique xenogeneic breast cancer model to study the effects of tumor cells and neighboring host cells upon each other in tumor growth and metastasis. It exploited species differences between the interacting components to determine how the host influenced the tumor and vice versa. It was found that the gene expression profiles of highly and poorly metastatic clones from the same human breast carcinoma changed differentially when the cells were transferred from growth in vitro to the mammary gland. We describe novel sets of genes, validated by human-specific probes, which were induced in the 2 isogenic, but phenotypically different, tumor lineages by the mammary environment. Conversely, the tumor cells also induced changes in gene expression in the neighboring host stromal (i.e., mesenchymal) cell lineages, validated by mouse-specific probes. Reciprocal inductive interactions were also demonstrated in the tumor deposits formed preferentially in the lungs and lymph nodes by the highly metastatic tumor cells. Subtraction of the induced gene changes in the primary site from those in the metastases revealed that the number and magnitude of specific gene inductions in colonized organs were moderate. This finding indicates that the gene expression program causing metastasis has only limited flexibility and fits well with clinical observations that tumor cells form metastases preferentially in select organs, although tumor cells are scattered ubiquitously. This dependency on suitable host niches suggests new molecular therapeutic avenues that target genes in the host-support system that is manipulated by the malignant cells. To survive and prevail, the intruding cells must co-opt local conditions to provide their needs. This prompts questions about what interactions and mechanisms are activated to promote this disorderly behavior and how these are normally suppressed.The discoveries of Spemann and colleagues, 1 that cells of different embryonic lineages actively induce each other to cooperate in the formation of tissues, organs and body regions have far reaching applications in solving such fundamental but clinically relevant questions. Their findings provided a rational framework for explaining how specialized cell lineages interact to produce and maintain the anatomic plan of the whole animal and the microscopic architecture of its individual organs throughout life and healing processes. Conversely, their observations also have important implications for understanding mechanisms underlying the progressive histological disorganization which characterizes cancer pathogenesis and progression to metastatic malignancy. Important steps in recognizing the importance of cell and tissue interactions in neoplasia include the work of Orr that showed that morphological 2 and functional 3 changes occur in the dermis of carcinogen-treated skin long before a carcinoma develops from the overlying epidermis. Later, Grobstein 4 and Sengel et al. 5 showed that the formation of the microscopic anatomy and histology of org...

Section: Discussionmentioning

confidence: 99%

Tumor–stromal interactions reciprocally modulate gene expression patterns during carcinogenesis and metastasis

Montel

Mose

Tarin

2006

“…5b) but was not evident in the nontumorigenic keratinocyte cell line HaCaT 19 treated with TNF-(20 ng/ml), TGF-␤1 (5 ng/ml) or IFN-␥ (100 U/ml) for 24 hr (data not shown). In addition, no expression of MMP-19 mRNA was detected in A5 cells, a rastransformed HaCaT cell-derived cell line that forms benign tumors 20 or in cutaneous SCC metastasis-derived UT-SCC-7 cells, which form SCCs in SCID mice 21 (data not shown). Although immortalized HaCaT cells are nontumorigenic, their MMP expression profile clearly differs from that of primary keratinocytes, e.g., MMP-12 and MMP-13, which are upregulated in the course of epithelial transformation and expressed by HaCaT cells but not by primary keratinocytes.…”

Section: Northern and Western Analyses Of Keratinocytesmentioning

confidence: 93%

“…The UT-SCC-7 cell line, which forms SCCs in SCID mice, 21 was established from metastasis of a cutaneous SCC at the time of operation in the Turku University Central Hospital. 22 Cell lines were cultured in DMEM supplemented with 6 mM glutamine, nonessential amino acids and 10% FCS.…”

Section: Cell Culturesmentioning

confidence: 99%

Matrix metalloproteinase‐19 is expressed by proliferating epithelium but disappears with neoplastic dedifferentiation

Impola

Toriseva

Suomela

et al. 2002

Self Cite

“…This suggests that TIMP-3 expressed by the AdTIMP-3 tumor cells was having a bystander effect on the untransduced tumor cells, illustrating that in the case of gene transfer systems, secreted proteins such as the TIMPs are advantageous as antiangiogenesis/anticancer agents. 139 The proapoptotic effects of TIMP-3 may mean that as well as acting as an antiangiogenic factor, this inhibitor could reduce tumor size by promoting tumor cell apoptosis. The potent affinity of TIMP-3 for the ECM means that this inhibitor will maintain local distribution, meaning higher concentrations of TIMP-3 at the site of the disease.…”

Section: Timps As Potential Antiangiogenic Agentsmentioning

confidence: 99%

Metalloproteinases and their inhibitors in tumor angiogenesis

Handsley

Edwards

2005

260

211

Angiogenesis is the process by which new blood vessels are formed from preexisting vasculature. It is an essential feature of the female reproductive cycle, embryonic development and wound repair. Angiogenesis has also been identified as a causal or contributing factor in several pathologies, including cancer, where it is a rate-limiting step during tumor progression. Matrix metalloproteinases (MMPs) are a family of soluble and membrane-anchored proteolytic enzymes that can degrade components of the extracellular matrix (ECM) as well as a growing number of modulators of cell function. Several of the MMPs, in particular the gelatinases and membrane-type 1 MMP (MT1-MMP), have been linked to angiogenesis. Potential roles for these proteases during the angiogenic process include degradation of the basement membrane and perivascular ECM components, unmasking of cryptic biologically relevant sites in ECM components, modulation of angiogenic factors and production of endogenous angiogenic inhibitors. This review brings together what is currently known about the functions of the MMPs and the closely related ADAM (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) families in angiogenesis and considers how this information might be useful in manipulation of the angiogenic process, with a view to constraining tumor progression. ' 2005 Wiley-Liss, Inc.Key words: metalloproteinase; tumor; angiogenesis; tissue inhibitor of metalloproteinases; protease; extracellular matrix Angiogenesis is an essential feature of several physiologic processes such as the developmental growth of organs, wound healing and the female reproductive cycle. 1 It is also particularly significant in cancer progression, being a crucial step in the transition of a tumor from a hyperplastic but contained in situ state to a malignant phenotype. 2,3 To allow its growth beyond a certain critical size, a solid avascular tumor must develop its own blood supply in order to meet its growing metabolic requirements. 1 Vascularization of a tumor also provides a route for dissemination of the tumor cells to different sites around the body.Although angiogenesis appears to be the primary form of tumor vascularization, the malignant cells of a tumor can gain access to a blood supply through other means, such as via tumor-induced vasculogenesis, in which bone marrow-derived precursor endothelial cells contribute to the formation of tumor vessels. 4,5 Vasculogenic mimicry is another form of vessel formation that has been reported in certain tumor types, such as aggressive human uveal melanomas, prostate and breast tumors. [6][7][8] In these cases, networks of tumor cell-lined vascular channels were identified within the tumors. Finally, vessel co-option, implemented by tumor cells as a temporary means of gaining access to a blood supply, involves the tumor cells growing around and thus co-opting existing host vessels to form an initially well-vascularized tumor. 9 This review will highlight new insigh...