Article

Preparing the "Soil": The Premetastatic Niche

Cell and Developmental Biology, Cornell University, Итак, New York, United States
Cancer Research (Impact Factor: 9.33). 01/2007; 66(23):11089-93. DOI: 10.1158/0008-5472.CAN-06-2407
Source: PubMed

ABSTRACT

Current focus on cancer metastasis has centered on the intrinsic factors regulating the cell autonomous homing of the tumor cells to the metastatic site. Specific up-regulation of fibronectin and clustering of bone marrow-derived cellular infiltrates coexpressing matrix metalloproteinases in distant tissue sites before tumor cell arrival are proving to be indispensable for the initial stages of metastasis. These bone marrow-derived hematopoietic progenitors that express vascular endothelial growth factor receptor 1 mobilize in response to the unique array of growth factors produced by the primary tumor. Their arrival in distant sites represents early changes in the local microenvironment, termed the "premetastatic niche," which dictate the pattern of metastatic spread. Focus on the early cellular and molecular events in cancer dissemination and selectivity will likely lead to new approaches to detect and prevent metastasis at its earliest inception.

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    • "The expression of VEGFR1 on these macrophages is associated with a more aggressive clinical phenotype of breast cancer [3]. Finally, in response to chemokine activity within the primary tumor, VEGFR1 positive hematopoietic progenitor cells preferentially localize to pre-metastatic sites [4]. Because of the involvement of VEGFR1 in cancer pathogenesis, our goal is to develop high affinity antibodies for molecular imaging or molecularly targeted therapy of cancer. "
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    ABSTRACT: VEGFR1 is a receptor tyrosine kinase that has been implicated in cancer pathogenesis. It is upregulated in angiogenic endothelial cells and expressed on human tumor cells as well. VEGFR1 positive hematopoietic progenitor cells home to sites of distant metastases prior to the arrival of the tumor cells thus establishing a pre-metastatic niche. To discover high affinity human antibodies selective for VEGFR1 molecular imaging or for molecularly targeted therapy, a novel phage display scFv library was assembled and characterized. The library was constructed from the humanized 4D5 framework that was mostly comprised tyrosine and serine residues in four complimentarity determining regions (CDRs). The library produced diverse and functional antibodies against a panel of proteins, some of which are of biomedical interest including, CD44, VEGFA, and VEGFR1. After panning, these antibodies had affinity strong enough for molecular imaging or targeted drug delivery without the need for affinity maturation. One of the anti-VEGFR1 scFvs recognized its cognate receptor and was selective for the VEGFR1.
    Preview · Article · Aug 2015
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    • "Recent studies on the metastatic process have suggested that the tumor micro- and macro-environments may play critical roles in metastatic dissemination [reviewed in Ref. (172, 173)]. One of the more novel concepts is that of the pre-metastatic niche, where the innate immune system plays a key role (41, 42, 174). Attenuation of NK cell activity is associated with generation of the pre-metastatic niche and metastasis efficiency in murine models (40), where conditioned media from hypoxic tumor cells was associated with increased NK recruitment and reduced NK cytolytic activity. "
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    ABSTRACT: It is widely accepted that the tumor microenvironment (TUMIC) plays a major role in cancer and is indispensable for tumor progression. The TUMIC involves many "players" going well beyond the malignant-transformed cells, including stromal, immune, and endothelial cells (ECs). The non-malignant cells can acquire tumor-promoting functions during carcinogenesis. In particular, these cells can "orchestrate" the "symphony" of the angiogenic switch, permitting the creation of new blood vessels that allows rapid expansion and progression toward malignancy. Considerable attention within the context of tumor angiogenesis should focus not only on the ECs, representing a fundamental unit, but also on immune cells and on the inflammatory tumor infiltrate. Immune cells infiltrating tumors typically show a tumor-induced polarization associated with attenuation of anti-tumor functions and generation of pro-tumor activities, among these angiogenesis. Here, we propose a scenario suggesting that the angiogenic switch is an immune switch arising from the pro-angiogenic polarization of immune cells. This view links immunity, inflammation, and angiogenesis to tumor progression. Here, we review the data in the literature and seek to identify the "conductors" of this "orchestra." We also suggest that interrupting the immune → inflammation → angiogenesis → tumor progression process can delay or prevent tumor insurgence and malignant disease.
    Full-text · Article · Jul 2014 · Frontiers in Oncology
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    • "Increasing evidence supports the prometastatic functions of the microenvironment, with many studies indicating the importance of bone marrow cells in the metastatic niche. Many early studies have shown that these bone marrow cells set up a metastatic niche at the secondary site that allows for cells to establish [1] [2]. Subsequent studies have specifically isolated myeloid-derived suppressor cells [3] [4] [5] [6], myofibroblast [7] [8] [9], and tumor-associated macrophages [10] [11] [12]. "
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    ABSTRACT: Tumor-induced bone disease is a dynamic process that involves interactions with many cell types. Once metastatic cancer cells reach the bone, they are in contact with many different cell types that are present in the cell-rich bone marrow. These cells include the immune cells, myeloid cells, fibroblasts, osteoblasts, osteoclasts, and mesenchymal stem cells. Each of these cell populations can influence the behavior or gene expression of both the tumor cells and the bone microenvironment. Additionally, the tumor itself can alter the behavior of these bone marrow cells which further alters both the microenvironment and the tumor cells. While many groups focus on studying these interactions, much remains unknown. A better understanding of the interactions between the tumor cells and the bone microenvironment will improve our knowledge on how tumors establish in bone and may lead to improvements in diagnosing and treating bone metastases. This review details our current knowledge on the interactions between tumor cells that reside in bone and their microenvironment.
    Full-text · Article · Jun 2014 · BioMed Research International
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