Radial Scars in Benign Breast-Biopsy Specimens and the Risk of Breast Cancer

Jacobs, Timothy W.; Byrne, Celia; Colditz, Graham A.; Connolly, James L.; Schnitt, Stuart J.

doi:10.1056/nejm199902113400604

Cited by 310 publications

(181 citation statements)

References 26 publications

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“…Recent clinical studies indicate that chemotherapy for hepatocarcinoma could be more effective if therapies to target the underlying liver fibrosis were also employed 120,121 . As fibrotic breast disease is also associated with a predisposition to breast cancer 122 , and environmentally induced fibrotic disorders of the lung can increase incidence of lung cancer 123 , targeting the tumour environment might also increase the treatment effectiveness for these types of cancer.…”

Section: Targeting the Tumour Organmentioning

confidence: 99%

Putting tumours in context

2001

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The interactions between cancer cells and their micro-and macroenvironment create a context that promotes tumour growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets.Under normal conditions, ORGANS are made up of TISSUES that exchange information with other cell types via cell-cell contact, cytokines and the EXTRACELLULAR MATRIX (ECM). The ECM, which is produced by collaboration between STROMAL fibroblasts and EPITHELIAL cells, provides structural scaffolding for cells, as well as contextual information. The endothelial vasculature provides nutrients and oxygen, and cells of the immune system combat pathogens and remove apoptotic cells. Epithelial cells associate into intact, polarized sheets. These tissues communicate through a complex network of interactions: physically, through direct contact or through the intervening ECM, and biochemically, through both soluble and insoluble signalling molecules. In combination, these interactions provide the information that is necessary to maintain cellular differentiation and to create complex tissue structures.Occasionally, the intercellular signals that define the normal context become disrupted. Alterations in epithelial tissues can lead to movement of epithelial sheets and proliferationfor example, after activation of mesenchymal fibroblasts due to wounding. Normally, these conditions are temporary and reversible, but when inflammation is sustained, an escalating feedback loop ensues. Under persistent inflammatory conditions, continual upregulation of enzymes such as matrix metalloproteinases (MMPs) by stromal fibroblasts can disrupt the ECM, and invading immune cells can overproduce factors that promote abnormal proliferation.As this process progresses, the normal organization of the organ is replaced by a functional disorder (FIG. 1). If there are pre-existing epithelial cells within this changing context that possess tumorigenic potential, they can start to proliferate. Alternatively, the abnormal An innate anticancer mechanismAn important feature of the normal stromal context is the generation and maintenance of epithelial-cell polarity. Epithelial cells receive a variety of orientational cues from the environment that help them establish cellular apical and basal surfaces and to maintain the differentiated state. Loss of polarity has been shown to lead to increased cell proliferation and tumorigenesis (BOX 1). The basal surface of epithelial cells associates with the BASEMENT MEMBRANE, a specialized form of ECM that provides both structural support and polarization signals to epithelia. The basement membrane is a dynamic structure. Changes in its composition lead to changes in cell shape and behaviour 1 , altered binding affinity or cellular distribution of cell-surface receptors 2 , and cellu...

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Section: Targeting the Tumour Organmentioning

confidence: 99%

Putting tumours in context

2001

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“…In addition, an altered stromal environment may actually promote neoplastic transformation (Jacobs et al, 1999;Jacoby et al, 1997;Kinzler and Vogelstein, 1998;Willenbucher et al, 1999). Indeed, stromal changes appeared to presage malignant epithelial changes in the WAP-Str1 transgenic mice (Thomasset et al, 1998).…”

Section: How Mmps Might Promote Tumor Developmentmentioning

confidence: 99%

“…Expression of the Str1 transgene during pregnancy and lactation also led to enhanced expression of endogenous Str1 by mammary ®broblasts, collagen accumulation (®brosis), neovascularization, and tenascin-C expression (Thomasset et al, 1998). These changes are not only hallmarks of the reactive stroma seen during involution, but are also seen during cancer progression (Borsi et al, 1992;Rùnnov-Jessen et al, 1996) and may even predispose toward neoplastic epithelial transformation (Jacobs et al, 1999;Jacoby et al, 1997;Kinzler and Vogelstein, 1998;Willenbucher et al, 1999). Furthermore, the proliferative e ects of Str1 could support neoplastic transformation and its apoptotic e ects could help select apoptosis-resistant clones.…”

Section: Introductionmentioning

confidence: 99%

The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter

2000

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Extracellular matrix-degrading matrix metalloproteinases (MMPs) are invariably upregulated in epithelial cancers and are key agonists in angiogenesis, invasion and metastasis. Yet most MMPs are secreted not by the cancer cells themselves, but by stromal cells within and around the tumor mass. Because the stromal environment can in¯uence tumor formation, and because MMPs can alter this environment, MMPs may also contribute to the initial stages of cancer development. Several recent studies in MMP-overexpressing and MMP-de®cient mice support this possibility, but have required carcinogens or pre-existing oncogenic mutations to initiate tumorigenesis. Here we review the spontaneous development of premalignant and malignant lesions in the mammary glands of transgenic mice that express an autoactivating form of MMP-3/stromelysin-1 under the control of the whey acidic protein gene promoter. These changes were absent in nontransgenic littermates and were quenched by co-expression of a human tissue inhibitor of metalloproteinases-1 (TIMP-1) transgene. Thus by altering the cellular microenvironment, stromelysin-1 can act as a natural tumor promoter and enhance cancer susceptibility.

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“…1,2 The significant contribution of stroma to the development of a wide variety of tumors has been supported by extensive clinical evidence; this contribution is highlighted by the higher incidence of tumor formation in tissues exhibiting a chronically inflamed stroma as well as those undergoing various types of wound healing, in which the stroma plays a central role. 3,4 Use of mouse models of tumorigenesis also reveals that stromal cells, notably inflammatory cells, vascular cells, and fibroblasts, [5][6][7][8] actively support tumor growth.…”

Section: Introductionmentioning

confidence: 99%

Stromal Fibroblasts in Cancer: A Novel Tumor-Promoting Cell Type

Orimo¹,

Weinberg²

2006

Cell Cycle

739

581

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Tumors are highly complex tissues composed of neoplastic cells and, in the case of carcinomas, stromal cell compartments containing a variety of mesenchymal cells, notably fibroblasts, myofibroblasts, endothelial cells, pericytes, and a variety of inflammatory cells associated with the immune system. Fibroblasts and myofibroblasts often represent the majority of the stromal cells within various types of human carcinomas, yet the specific contributions of these cells to tumor growth are poorly understood. Recent work has demonstrated that stromal fibroblast fractions, named carcinoma-associated fibroblasts (CAFs), that have been extracted from a number of invasive human breast carcinomas are more competent to promote the growth of mammary carcinoma cells and to enhance tumor angiogenesis than are comparable cells derived from outside of these tumor masses. CAFs include large populations of myofibroblasts that secrete elevated levels of stromal cell-derived factor 1 (SDF-1), also called CXCL12, which plays a central role in the promotion of tumor growth and angiogenesis; CAF-derived SDF-1 not only stimulates carcinoma cell growth directly through the CXCR4 receptor displayed on tumor cells but also serves to recruit endothelial progenitor cells (EPCs) into tumors, thereby furthering neoangiogenesis. In this review, we highlight the importance of this SDF-1-CXCR4 signaling pathway in the tumor microenvironment and discuss the mechanisms by which stromal fibroblasts within mammary carcinomas enhance tumor growth.

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Radial Scars in Benign Breast-Biopsy Specimens and the Risk of Breast Cancer

Cited by 310 publications

References 26 publications

Putting tumours in context

Putting tumours in context

The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter

Stromal Fibroblasts in Cancer: A Novel Tumor-Promoting Cell Type

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