The Basic Biology of Metastasis

Robinson, Victoria; Kauffman, Eric; Sokoloff, Mitchell H.; Rinker‐Schaeffer, Carrie W.

doi:10.1007/978-1-4419-9129-4_1

Cited by 23 publications

(11 citation statements)

References 68 publications

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“…Metastasis suppressors can impart their suppressive activity at one or more of the steps in the metastatic cascade (6). For example, in vivo studies showed that metastatic cancer cells which express ectopic KISS1, JNKK1/MKK4, MKK6, MKK7, TXNIP, nm23-H1, or SSeCKS proteins could successfully disseminate and lodge at secondary sites, but are suppressed in their ability to colonize (i.e., form overt metastases) target tissues (7 -12).…”

Section: Functional Identification Of Metastasis Suppressorsmentioning

confidence: 99%

Metastasis Suppressor Proteins: Discovery, Molecular Mechanisms, and Clinical Application

Rinker‐Schaeffer

O’Keefe

Welch

et al. 2006

Clinical Cancer Research

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119

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Clinically and experimentally, primary tumor formation and metastasis are distinct processes -locally growing tumors can progress without the development of metastases. This observation prompted the hypothesis that the molecular processes regulating tumorigenicity and metastasis are distinguishable and could be targeted therapeutically. During the process of transformation and subsequent progression to a malignant phenotype, both genetic and epigenetic alterations alter a cell's ability to perceive and respond to signals that regulate normal tissue homeostasis. A minority of tumorigenic cells accrue the full complement of alterations that enables them to disseminate from the primary tumor, survive insults from the immune system and biophysical forces, and respond to growthpromoting and/or inhibitory signals from the distant tissues and thrive there. Identification of genes and proteins that specifically inhibit the ability of cells to form metastases (e.g., metastasis suppressors) is providing new insights into the molecular mechanisms that regulate this complex process. This review will highlight: (a) the functional identification of metastasis suppressors, (b) the signaling cascades and cellular phenotypes which are controlled or modulated by metastasis suppressors, and (c) opportunities for translation and clinical trials that are based on mechanistic studies regarding metastasis suppressors.

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Section: Functional Identification Of Metastasis Suppressorsmentioning

confidence: 99%

Metastasis Suppressor Proteins: Discovery, Molecular Mechanisms, and Clinical Application

Rinker‐Schaeffer

O’Keefe

Welch

et al. 2006

Clinical Cancer Research

Self Cite

119

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“…A majority of patients dying from prostate or breast tumors have bone metastases [1,2]. The affinity of PCa tumor cells to bone is probably a consequence of the specific microenvironment provided by the bone, and the fact that bone matrix is a rich storehouse of growth factors [3,4]. The stored factors can be mobilized by the bone remodeling process and enrich the local environment with a variety of tumor cell stimulating factors.…”

Section: Introductionmentioning

confidence: 98%

Establishment and validation of an in vitro co-culture model to study the interactions between bone and prostate cancer cells

Nordstrand

Nilsson

Tieva

et al. 2009

Clin Exp Metastasis

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Bone is the preferred site for prostate cancer (PCa) metastases. Once the tumor has established itself within the bone there is virtually no cure. To better understand the interactions between the PCa cells and bone environment in the metastatic process new model systems are needed. We have established a two-compartment in vitro co-culturing model that can be used to follow the trans-activation of bone and/or tumor cells. The model was validated using two PCa tumor cell lines (PC-3; lytic and LNCaP; mixed/osteoblastic) and one osteolytic inducing factor, 1,25-dihydroxyvitamin D(3) (D3). Results were in accordance with the expected bone phenotypes; PC-3 cells and D3 gave osteolytic gene expression profiles in calvariae, with up-regulation of genes needed for osteoclast differentiation, activation and function; Rankl, CathK, Trap and MMP-9, and down-regulation of genes associated with osteoblast differentiation and bone mineralization; Alp, Ocl and Dkk-1. LNCaP cells activated genes in the calvarial bones associated with osteoblast differentiation and mineralization, with marginal effects on osteolytic genes. The results were strengthened by similar changes in protein expression for a selection of the analyzed genes. Furthermore, the osteolytic gene expression profiles in calvarial bones co-cultured with PC-3 cells or with D3 were correlated with the actual ongoing resorptive process, as assessed by the release of collagen fragments from the calvariae. Our results show that the model can be used to follow tumor-induced bone remodeling, and by measuring changes in gene expression in the tumor cells we can also study how they respond to the bone microenvironment.

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“…Two thirds of the cancer-related deaths in the US involve bone metastasis [1,2]. ARCaP cells, isolated from the ascites fluid of a patient with bone metastasis, express a host of human prostate cancer biomarkers, have high propensity for rapid and predictable bone and soft tissue growth/metastases through orthotopic, intracardic and intraosseous injections [3][4][5], and undergo EMT on exposure to soluble factors or host bone microenvironment [4,6].…”

Section: Introductionmentioning

confidence: 99%

Epithelial to mesenchymal transition (EMT) in human prostate cancer: lessons learned from ARCaP model

Zhau

Odero-Marah

Lue

et al. 2008

Clin Exp Metastasis

135

156

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Androgen refractory cancer of the prostate (ARCaP) cells contain androgen receptor (AR) and synthesize and secrete prostate specific antigen (PSA). We isolated epithelia-like ARCaP(E) from parental ARCaP cells and induced them to undergo epithelial-mesenchymal transition (EMT) by exposing these cells to soluble factors including TGFbeta1 plus EGF, IGF-1, beta2-microglobulin (beta2-m), or a bone microenvironment. The molecular and behavioral characteristics of the resultant ARCaP(M) were characterized extensively in comparison to the parental ARCaP(E) cells. In addition to expressing mesenchymal biomarkers, ARCaP(M) gained 100% incidence of bone metastasis. ARCaP(M) cells express receptor activator of NF-kappaB ligand (RANKL), which was shown to increase tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in culture, and when metastatic to bone in vivo. We provide evidence that RANKL expression was promoted by increased cell signaling mediated by the activation of Stat3-Snail-LIV-1. RANKL expressed by ARCaP(M) cells is functional both in vitro and in vivo. The lesson we learned from the ARCaP model of EMT is that activation of a specific cell signaling pathway by soluble factors can lead to increased bone turnover, mediated by enhanced RANKL expression by tumor cells, which is implicated in the high incidence of prostate cancer bone colonization. The ARCaP EMT model is highly attractive for developing new therapeutic agents to treat prostate cancer bone metastasis.

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The Basic Biology of Metastasis

Cited by 23 publications

References 68 publications

Metastasis Suppressor Proteins: Discovery, Molecular Mechanisms, and Clinical Application

Metastasis Suppressor Proteins: Discovery, Molecular Mechanisms, and Clinical Application

Establishment and validation of an in vitro co-culture model to study the interactions between bone and prostate cancer cells

Epithelial to mesenchymal transition (EMT) in human prostate cancer: lessons learned from ARCaP model

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