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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By deliberate analogy with the well-established concept of hematopoiesis, the term "mammopoiesis" is occasionally used to describe the development of the different cellular lineages and functional units in the mammary gland. The use of this term signifies a strong bias towards the idea that tissue homeostasis during mammary development, pregnancy, lactation and involution is brought about by the action of somatic stem cells characterized by longevity and multipotency. The progenies hereof eventually differentiate into structurally and functionally well-defined ductal-lobular units. During the past two decades evidence of such a notion in the mouse has developed from being largely circumstantial based on non-clonal in vivo experiments to a quite elaborate characterization of individual candidate stem cells by a number of different properties. Within tumor biology this has led to a renaissance of the concept of tumors as caricatures of tissue renewal. Thus, recent molecular classification of breast cancer based on genome wide expression analysis operates with different subtypes with specific reference to the normal luminal epithelial and myoepithelial/basal lineages in the breast. Apparently some tumors are lineage restricted and others differentiate more broadly as if they have preserved some stem-like properties. This holds promise for the existence of a stem cell hierarchy, the understanding of which may prove to be instrumental in further dissecting the histogenesis of breast cancer evolution. Most attention has been devoted to the question of different cellular origins of cancer subtypes and different susceptibilities of possible stem cells to gain or loss of oncogenes and tumor suppressor genes, respectively. Invaluable progress has been made over the past two decades in culture technology not only in terms of population doubling and clonal growth, but also the availability of lineage specific markers, cell sorting, and three-dimensional functional assays for tissue specific morphogenesis. Transcriptional profiling of stem cell zones has unraveled a hitherto unknown preservation of signaling pathways for maintenance of stem cell properties across tissue boundaries and species. Somatic stem cells have therefore been narrowed down to specific anatomic locations not only in rapidly renewing tissues such as skin and skin derivatives, but also in tissues with slower turnover times, such as lung, kidney and prostate. It is therefore now possible to integrate this information in a search for similar cells within the breast. Even if cell turnover after birth is provided exclusively by dividing lineage-restricted cells, more information about the robustness of breast differentiation programs during tumor progression is still very much required. Complete knowledge of the primary cell of origin of breast cancer and the mechanisms that influence differentiation programs during tumor initiation, promotion and progression may be crucial for the development of novel non-toxic therapies that influence tumor cell behaviour. The scope of this review is to discuss reports that have begun to elucidate the topographic location, key cellular type and lineage fidelity in culture and xenograft models of candidate human breast stem cells and their differentiated progenies with particular emphasis on comparison with the differentiation programs of tumor subtypes.
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PMID:In search of a stem cell hierarchy in the human breast and its relevance to breast cancer evolution. 1648 Apr 57

Although almost two decades of study point to a central role for aberrant ErbB2 activation in breast cancer, many cellular and biochemical mechanisms underlying ErbB2-induced tumor initiation and progression remain to be resolved. A study by Guo et al. published recently in Cell indicates that the signaling function of beta4 integrin actively contributes to the initiation, growth, and invasion of ErbB2-induced mammary tumors in transgenic mice by promoting the activation of c-Jun and STAT3. These observations offer novel mechanistic insight into ErbB2 action and highlight the notion that ErbB2 co-opts the functions of other signaling proteins to elicit tumor progression.
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PMID:Co-opted integrin signaling in ErbB2-induced mammary tumor progression. 1690 7

It is becoming accepted that multiple cell types in stromal microenvironment are involved in tumorigenesis. In this setting, mast cells (MC) display a diversity of roles that may contribute to the defense against tumors or tumor progression. Thus, the aim of this study was to evaluate density and migration of MCs in OSCC (oral squamous cell carcinoma) and pre-malignant oral hyperkeratosis (leukoplakia) as well as their relationship with clinical and microscopic parameters. The tryptase and c-kit expression was analyzed in 38 cases of OSCC, 26 cases of leukoplakia, and 12 cases of clinically healthy oral mucosa (control) by means of immunohistochemistry. The tryptase(+) cell numbers were decreased in OSCC (P=0.0003) and leukoplakia (P=0.03) compared with control. Similar numbers of tryptase(+) cells were observed in leukoplakia and OSCC (P=0.31). The density of c-kit(+) MCs was also significantly lower in OSCC and leukoplakia in relation to control resulting in a reduced c-kit(+)/tryptase(+) relationship in OSCC (19%) in comparison with leukoplakia (59%) and control (63%). No correlation was observed between MC populations with clinical and microscopic characteristics of OSCC. Our findings suggest that the decrease in MC numbers in pre-malignant and malignant oral lesions may be related to the migration failure of these cells, possibly reflecting an important modification in the microenvironment during tumor initiation and progression.
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PMID:Decrease in mast cells in oral squamous cell carcinoma: possible failure in the migration of these cells. 1697 74

Overexpression of the pituitary tumor-transforming gene (PTTG) has been associated with tumorigenesis. In a mouse model that spontaneously develops follicular thyroid cancer (FTC) with distant metastasis (TRbetaPV mouse), PTTG is overexpressed, similar to human thyroid cancer. To evaluate the role of PTTG in thyroid carcinogenesis, we studied the offspring of TRbetaPV mice with mice lacking PTTG (PTTG(-/-) mice). The thyroids of TRbeta(PV/PV) PTTG(-/-) mice were significantly smaller than TRbeta(PV/PV) mice. Ki-67 staining showed a decrease in thyroid proliferation in TRbeta(PV/PV) PTTG(-/-) mice. Our evaluation of the Rb-E2F pathway, a central mediator of cell growth, found that TRbeta(PV/PV) PTTG(-/-) mice exhibited a decrease in protein levels of phosphorylated Rb along with an elevation of the cdk inhibitor p21. Histological examination documented no difference in FTC occurrence between TRbeta(PV/PV) and TRbeta(PV/PV) PTTG(-/-) mice, which indicates that PTTG removal does not prevent the initiation of FTC. However, TRbeta(PV/PV) PTTG(-/-) mice had a significant decrease in vascular invasion and less development of lung metastasis as they progressively aged. CD31 staining also showed a decrease in vessel density in TRbeta(PV/PV) PTTG(-/-) versus TRbeta(PV/PV) thyroids. Given the decreased vascular invasion in the PTTG knockout mice, we studied genes involved in angiogenesis. Real-time reverse transcription-polymerase chain reaction showed a consistent decrease in pro-angiogenic factors, fibroblast growth factor (FGF2), its receptor FGFR1 and vascular endothelial growth factor. Our results highlight the dual roles of PTTG as a regulator of thyroid growth and contributor to tumor progression. The separation of the pathways regulating cell proliferation, tumor initiation and tumor progression should direct future therapeutic options.
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PMID:The pituitary tumor-transforming gene promotes angiogenesis in a mouse model of follicular thyroid cancer. 1712 11

Tumor progression and metastasis are the pathologic effects of uncontrolled or deregulated invasive growth, a process in which proteases play a fundamental role. They mediate the degradation of extracellular matrix components and intercellular cohesive structures to allow migration of the cells into the extracellular environment and activate growth and angiogenic factors. In addition to metalloproteases and the plasminogen activation system, another protease, matriptase, contributes substantially to these processes. Matriptase is a type II transmembrane trypsin-like serine protease that is expressed by cells of epithelial origin and is overexpressed in a variety of human cancers. It has been suggested that this protease not only facilitates cellular invasiveness but may also activate oncogenic pathways. This review summarizes current knowledge about matriptase, its putative role in tumor initiation and progression, and its potential as a novel target in anti-cancer therapy.
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PMID:Matriptase and its putative role in cancer. 1713 Oct 55

Adaptation to hypoxia is a critical step in tumor progression and is, in part, regulated by the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha). Xenograft models have been extensively used to characterize the role of HIF-1alpha in experimental cancers. Although these models provide an understanding of tumor growth at terminal stages of malignancy, they do not address tumor initiation or metastatic progression. To elucidate these roles, HIF-1alpha was conditionally deleted in the mammary epithelium of a transgenic mouse model for metastatic breast cancer. Conditional deletion of HIF-1alpha in the mammary epithelium resulted in delayed tumor onset and retarded tumor growth; this was correlated with decreased tumor cell proliferation. Tumors with conditional deletion of HIF-1alpha were also less vascular during early tumor progression. Perhaps most surprisingly, deletion of HIF-1alpha in the mammary epithelium resulted in decreased pulmonary metastasis. These results show that whereas HIF-1alpha is not required for the initiation of breast tumor growth or tumor cell metastasis, the transcriptional activity of HIF-1alpha is a significant positive regulator of tumor progression and metastatic potential.
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PMID:Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression. 1723 64

In a subset of gliomas, the platelet-derived growth factor (PDGF) signaling pathway is perturbed. This is usually an early event occurring in low-grade tumors. In high-grade gliomas, the subsequent loss of the INK4a-ARF locus is one of the most common mutations. Here, we dissected the separate roles of Ink4a and Arf in PDGFB-induced oligodendroglioma development in mice. We found that there were differential functions of the two tumor suppressor genes. In tumors induced from astrocytes, both Ink4a-loss and Arf-loss caused a significantly increased incidence compared to wild-type mice. In tumors induced from glial progenitor cells there was a slight increase in tumor incidence in Ink4a-/- mice and Ink4a-Arf-/- mice compared to wild-type mice. In both progenitor cells and astrocytes, Arf-loss caused a pronounced increase in tumor malignancy compared to Ink4a-loss. Hence, Ink4a-loss contributed to tumor initiation from astrocytes and Arf-loss caused tumor progression from both glial progenitor cells and astrocytes. Results from in vitro studies on primary brain cell cultures suggested that the PDGFB-induced activation of the mitogen-activated protein kinase pathway via extracellular signal-regulated kinase was involved in the initiation of low-grade oligodendrogliomas and that the additional loss of Arf may contribute to tumor progression through increased levels of cyclin D1 and a phosphoinositide 3-kinase-dependent activation of p70 ribosomal S6 kinase causing a strong proliferative response of tumor cells.
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PMID:Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma. 1743 29

It has been established that cancer can be promoted and/or exacerbated by inflammation and infections. Indeed, chronic inflammation orchestrates a tumor-supporting microenvironment that is an indispensable participant in the neoplastic process. The mechanisms that link infection, innate immunity, inflammation, and cancer are being unraveled at a fast pace. Important components in this linkage are the cytokines produced by activated innate immune cells that stimulate tumor growth and progression. In addition, soluble mediators produced by cancer cells recruit and activate inflammatory cells, which further stimulate tumor progression. However, inflammatory cells also produce cytokines that can limit tumor growth. Here we provide an overview of the current understanding of the role of inflammation-induced cytokines in tumor initiation, promotion, and progression.
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PMID:A cytokine-mediated link between innate immunity, inflammation, and cancer. 1747 47

Increasing evidence points to an active stromal involvement in cancer initiation and progression. Cytokines derived from tumor cells are believed to modulate stromal cells to produce growth and angiogenic factors, which in turn provide the tumor with the necessary microenvironment for expansion and invasion. Transforming growth factor beta (TGFbeta) has been implicated as a candidate cytokine to mediate this communication. However, how its signaling in stromal cells regulates tumorigenesis and tumor progression remains unresolved. We show that normal, presenescent fibroblasts or prostate stromal cells cotransplanted with prostate carcinoma cells s.c. into nude mice reduced tumor latency and accelerated tumor growth. When their TGFbeta signaling was blocked, the fibroblasts and stromal cells still stimulated tumor initiation but no longer supported tumor growth as control cells did. The loss of the tumor growth-promoting activity of the stromal cells with attenuated TGFbeta signaling was not associated with altered cellular senescence or tumor angiogenicity. TGFbeta and the medium conditioned by the prostate carcinoma cells stimulated myofibroblast differentiation of the intact stromal cells, but not the stromal cells with attenuated TGFbeta signaling. Gene microarray and quantitative reverse transcription-PCR analyses showed that TGFbeta up-regulated a host of genes in stromal cells that are involved in tissue remodeling and wound healing. Thus, our study provides evidence for TGFbeta as a supporting agent in tumor progression through the induction of a perpetual wound healing process in the tumor microenvironment.
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PMID:Transforming growth factor-beta signaling in prostate stromal cells supports prostate carcinoma growth by up-regulating stromal genes related to tissue remodeling. 1757 40

This study examines the expression of the insulin-like growth factor type 1 receptor (IGF-1R) in colorectal neoplasia. Previous studies have shown that the IGF-1R is expressed at high levels in normal embryonic stem cells and in many cancer phenotypes. However, lower IGF-1R levels are expressed in some advanced cancer phenotypes. The timing of and the reasons for these changes in expression during the evolution of a cancer are not understood. Here, we examine IGF-1R expression in the evolution of colorectal cancer by means of Northern blotting and immunohistochemistry validated by tissue and reagent controls and Western blotting. We show for the first time that (1) in normal colorectal crypts, epithelial stem cells in the basal crypt region express high IGF-1R levels, which decrease to low levels when these cells migrate to and differentiate in the mid and upper crypt regions; (2) in tumor initiation in aberrant crypt foci, all of the transformed cells express high levels of the IGF-1R at stem cell levels throughout the crypt axis; (3) in tumor progression in adenomatous and cancerous crypts, tumor cells of an epithelial type morphology express high levels of the IGF-1R; (4) in advanced cancers, low levels of the IGF-1R are expressed in invasive foci where cancer cells dedifferentiate to a mesenchymal-type morphology and show a loss of cell adhesion. Interestingly, these cells can form an alternating pattern with mesenchymal type cells that show cell adhesion and high levels of IGF-1R expression. In summary, this study shows that high-level IGF-1R expression in colorectal neoplasia is initiated by an abnormality of stem cell programmed differentiation in the aberrant crypt focus. However, low-level IGF-1R expression is found in some invasive cancers where it is consequent to cancer cell dedifferentiation to a mesenchymal type morphology with loss of cell adhesion.
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PMID:The insulin-like growth factor type 1 receptor and colorectal neoplasia: insights into invasion. 1765 87


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