CCN6 (WISP3) decreases ZEB1-mediated EMT and invasion by attenuation of IGF-1 receptor signaling in breast cancer

Hiles, Guadalupe Lorenzatti; Huang, Wei; Pal, Anupama; Cabanillas, Ana M.; Kleer, Celina G.

doi:10.1242/jcs.084194

Cited by 57 publications

(73 citation statements)

References 33 publications

(55 reference statements)

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“…Consistently, when ZEB1 is down-regulated through the use of siRNA, the epithelial phenotype of the cancer cells is restored as demonstrated by epitheliallike changes in cell morphology and E-cadherin andcatenin re-expression [111]. This finding is also consistent with other studies that showed a similar effect of IGF-I in inducing EMT-mediated invasion through regulating the ZEB1 expression in colorectal and breast cancer [112,113].…”

Section: The Role Of Igf System In Mediating Emtsupporting

confidence: 89%

The Role of the IGF Axis in Epithelial-to-Mesenchymal Transition during the Progression of Prostate Cancer

Mansor¹,

Bahl²,

Holly³

et al. 2015

J. Anal. Oncol.

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Prostate cancer is the second most common lethal cancer in men worldwide. Despite the fact that the prognosis for patients with localized disease is good, many patients succumb to metastatic disease with the development of resistance to hormone treatments. This is normally termed castration-resistant prostate cancer (CRPC). The development of metastatic, castration-resistant prostate cancer has been associated with epithelial-to-mesenchymal transition (EMT), a process where cancer cells acquire a more mesenchymal phenotype with enhanced migratory potential, invasiveness and elevated resistance to apoptosis. The main event in EMT is the repression of epithelial markers such as E-cadherin and upregulation of mesenchymal markers such as N-cadherin, vimentin and fibronectin. The insulin-like growth factor (IGF) signalling axis is essential for normal development and maintenance of tissues, including that of the prostate, and dysregulation of this pathway contributes to prostate cancer progression and malignant transformation. It is becoming increasingly clear that one of the ways in which the IGF axis impacts upon cancer progression is through promoting EMT. This review will explore the role of EMT in prostate cancer progression with a specific focus on the involvement of the IGF axis and its downstream signalling pathways in regulating EMT in prostate cancer.Keywords: Epithelial-to-mesenchymal transition, insulin-like growth factor family, prostate cancer progression, lifestyle factors. PROSTATE CANCERProstate cancer is the second most common lethal cancer diagnosed in men. According to The American Cancer Society, it is estimated that more than 220 000 new cases of prostate cancer will occur in the United States during 2015 accounting for about 26% of all cancers in men with a mortality rate of 9%: the second highest cause of cancer deaths in men after lung cancer [1].Age is the biggest risk factor for PCa with the incidence of prostate cancer being higher in older men particularly in men aged 65 and above [2]. The incidence of, and mortality from, prostate cancer varies hugely within different racial and ethnic groups. Much higher incidence and death rates are reported in black men compared to other races [3,4]: the reasons underlying these observations are still unclear but both genetic and/or environmental influences may be involved. A number of epidemiology studies have also reported that family history is a risk factor for PCa-with approximately 5-10% of cases being attributable to inherited genetic factors or PCa susceptibility genes [5,6] The prognosis for patients with localized disease is good, however the morbidity and mortality for prostate cancer patients who develop metastatic disease is high [7]. Androgen deprivation therapy (ADT) which involves surgical or chemical castration plays an important role in the treatment and management of prostate cancer and is also utilised as an adjuvant or neo-adjuvant treatment for high-risk disease [8]. The response to the treatments is however temporary a...

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Section: The Role Of Igf System In Mediating Emtsupporting

confidence: 89%

The Role of the IGF Axis in Epithelial-to-Mesenchymal Transition during the Progression of Prostate Cancer

Mansor¹,

Bahl²,

Holly³

et al. 2015

J. Anal. Oncol.

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“…CCN2 is induced by hypoxia and promotes bone metastasis of breast cancer cells (4,98,99). Here, it should be noted that CCN6 is known to contrarily repress breast cancer invasion through multiple pathways (100,101). In contrast to that of CCN1 and CCN2, the role of CCN3 in vascular development has not yet been clearly established, in spite of its angiogenic property.…”

Section: Cardiovascular System and Angiogenesismentioning

confidence: 94%

The CCN family acting throughout the body: recent research developments

Kubota

Takigawa

2013

BioMolecular Concepts

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The animal body is composed of a variety of cells and extracellular matrices that are organized and orchestrated in a harmonized manner to support life. Therefore, the critical importance of a comprehensive understanding of the molecular network surrounding and integrating the cells is now emphasized. The CCN family is a novel group of matricellular proteins that interact with and orchestrate a number of extracellular signaling and matrix molecules to construct and maintain living tissues. This family comprises six distinct members in mammals, which are characterized by a unique and conserved modular structure. These proteins are not targeted to limited and specific receptors to execute specific missions, but manipulate a vast number of biomolecules in the network by serving as a molecular hub at the center. The unified nomenclature, CCN, originates from a simple acronym of the three classical members, which helps us to avoid having any preconception about their pleiotropic and anonymous functional nature. In this review, after a brief summary of the general molecular concepts regarding the CCN family, new aspects of each member uncovered by recent research are introduced, which represent, nevertheless, only the tip of the iceberg of the profound functionality of these molecules.

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“…Lorenzatti et al (2011) had essentially showed that exogenous CCN6 blunted the IGF1 signaling required to upregulate EMT and invasiveness of MDA-MB-231, suggesting CCN6 as a therapeutic target. Pal et al (2012a) followed up by identifying the signaling pathway partners BMP4-TAK1 using p38 kinases to regulate acinar morphogenesis and invasion of breast cancer cells.…”

Section: Ccn6 (Wisp-3)mentioning

confidence: 99%

CCN family of proteins: critical modulators of the tumor cell microenvironment

Yeger

Perbal

2016

J. Cell Commun. Signal.

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The CCN family of proteins consisting of CCN1 (Cyr61), CCN2 (CTGF), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2) and CCN6 (WISP-3) are considered matricellular proteins operating essentially in the extracellular microenvironment between cells. Evidence has also been gradually building since their first discovery of additional intracellular roles although the major activity is triggered at the cell membrane. The proteins consist of 4 motifs, a signal peptide (for secretion} followed consecutively by the IGFBP, VWC, TSP1 and CT (C-terminal cysteine knot domain) motifs, which signify their potential binding partners and functional connections to a variety of key regulators of physiological processes. With respect to cancer it is now clear that, whereas certain members can facilitate tumor behavior and progression, others can competitively counter the process. It is therefore clear that the net outcome of biological interactions in the matrix and what gets signaled or inhibited can be a function of the interplay of these CCN 1-6 proteins. Because the CCN proteins further interact with other key proteins, like growth factors in the matrix, the balance is not only important but can vary dynamically with the physiological states of tumor cells and the surrounding normal cells. The tumor niche with its many cell players has surfaced as a critical determinant of tumor behavior, invasiveness, and metastasis. It is in this context that CCN proteins should be investigated with the potential of being recognized and validated for future therapeutic approaches.

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CCN6 (WISP3) decreases ZEB1-mediated EMT and invasion by attenuation of IGF-1 receptor signaling in breast cancer

Cited by 57 publications

References 33 publications

The Role of the IGF Axis in Epithelial-to-Mesenchymal Transition during the Progression of Prostate Cancer

The Role of the IGF Axis in Epithelial-to-Mesenchymal Transition during the Progression of Prostate Cancer

The CCN family acting throughout the body: recent research developments

CCN family of proteins: critical modulators of the tumor cell microenvironment

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