Loss of WISP-2/CCN5 signaling in human pancreatic cancer: A potential mechanism for epithelial-mesenchymal-transition

Dhar, Gopal; Mehta, Smita; Banerjee, Snigdha; Gardner, Ashleigh; McCarty, Bryan; Mathur, Sharad C.; Campbell, Donald R.; Kambhampati, Suman; Banerjee, Sushanta K.

doi:10.1016/j.canlet.2007.02.012

Cited by 63 publications

(78 citation statements)

References 32 publications

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“…6, 7). Notably, our studies have established that CCN5 is a two-faced signaling molecule, and one of the major functions of the CCN5 protein is to block aggressive behavior, such as the mesenchymal-to-epithelial transition (MET), of cancer cells (8). These findings were further supported by a recent study (9).…”

Section: Introductionsupporting

confidence: 76%

Gain of Oncogenic Function of p53 Mutants Induces Invasive Phenotypes in Human Breast Cancer Cells by Silencing CCN5/WISP-2

et al. 2008

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CCN5/WISP-2 is overexpressed in noninvasive breast cancer cells and tissue samples, whereas its expression is minimal or undetected in invasive conditions. CCN5/WISP-2 has been considered as an antiinvasive gene because CCN5/WISP-2 silencing augments the invasive phenotypes in vitro. However, the mechanism of silencing of CCN5 during the progression of the disease has been elusive. Because p53 mutations are associated with breast cancer progression and have been shown to correlate inversely with CCN5/WISP-2 expression in other cancer cell types, the objective of this study was to explore whether p53 mutants suppress CCN5 expression in breast tumor cells resulting in the progression of this disease. We found CCN5 expression is inversely correlated with the mutational activation of p53 in human breast tumor cells. The ectopic expression of p53 mutants in ER-positive noninvasive breast tumor cells silenced the CCN5/WISP-2 expression and enhanced invasive phenotypes, including the induction of morphologic changes from the epithelial-to-mesenchymal type along with the alterations of hallmark proteins of these cell types and an augmentation of the migration of these cells. The suppression of CCN5 by the p53 mutants can be nullified by estrogen signaling in these cells through the transcriptional activation of the CCN5 gene. Moreover, the invasive changes can be imitated by blocking the CCN5/WISP-2 expression through RNA interference or can be reversed by the addition of CCN5/WISP-2 recombinant protein in the culture. Thus, these studies suggest that CCN5 inactivation could be an essential molecular event for p53 mutant-induced invasive phenotypes. [Cancer Res 2008;68(12):4580-7]

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Section: Introductionsupporting

confidence: 76%

Gain of Oncogenic Function of p53 Mutants Induces Invasive Phenotypes in Human Breast Cancer Cells by Silencing CCN5/WISP-2

et al. 2008

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“…This Gain of carcinogenic function of p53 tumor suppressor gene suppresses CCN5/WISP-2 expression in breast cancer cells Mutations (principally, but not exclusively, missense) in the p53 tumor suppressor gene are the most common genetic insult in breast cancer and these mutations are intimately associated with the aggressiveness of this disease and poor survival rates (Gasco et al 2002). Our studies found that over expression of the p53 mutant protein is inversely correlated with CCN5 expression in pancreatic cancer samples (Dhar et al 2007a) and breast cancer samples ). We also found that ectopic expression of p53 mutants suppresses CCN5 expression in breast cancer cell lines for the induction of invasive phenotypes, including the induction of morphologic changes from the epithelial-to-mesenchymal type along with the alterations of hallmark proteins of these cell types and an augmentation of the migration of these cells .…”

Section: Ccn5 Is a Negative Regulator Of Micro-rna 10bmentioning

confidence: 54%

CCN5/WISP-2: A micromanager of breast cancer progression

Banerjee

2012

J. Cell Commun. Signal.

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The gain of plasticity by a subset of cancer cells is a unique but common sequence of cancer progression from epithelial phenotype to mesenchymal phenotype (EMT) that is followed by migration, invasion and metastasis to a distant organ, and drug resistance. Despite multiple studies, it is still unclear how cancer cells regulate plasticity. Recent studies from our laboratory and others' proposed that CCN5/WISP-2, which is found intracellularly (in the nucleus and cytoplasm) and extracellularly, plays a negative regulator of plasticity. It prevents the EMT process in breast cancer cells as well as pancreatic cancer cells. Multiple genetic insults, including the gain of p53 mutations that accumulate over the time, may perturb CCN5 expression in non-invasive breast cancer cells, which ultimately helps cells to gain invasive phenotypes. Moreover, emerging evidence indicates that several oncogenic lesions such as miR10b upregulation and activation of TGF-β-signaling can accumulate during CCN5 crisis in breast cancer cells. Collectively, these studies indicate that loss of CCN5 activity may promote breast cancer progression; application of CCN5 protein may represent a novel therapeutic intervention in breast cancer and possibly pancreatic cancer. Keywords Breast cancer . Cell signaling . Invasion and apoptosis Human breast cancer: an overviewBreast cancer, a genetically heterogeneous disease (Lichy et al. 2000;Polyak 2011), is the most commonly identified malignant disease in Western women after nonmelanocytic skin cancer. It attacks one in eight women (~12%), impacting nearly every family worldwide. It is estimated that more than 1 in 4 cancers are breast cancer. Approximately 30% of these women will develop the invasive form of the disease, which is ultimately incurable. Therefore, it is a major health issue for women. Incidence of breast cancer generally increases with age. Women approaching or at menopause have an increased risk of breast cancer. In addition to age, several other factors (i.e., personal and environmental) are associated with the development of this disease. Fortunately, the breast cancer related death rate has been reduced recently due, in part, to early diagnosis and decreased intake of carcinogenic hormones or other unknown factors. However, our current therapeutic options for advanced stages of breast cancer are still fairly limited and ineffective. Thus, there is a need to better understand the molecular basis of the genesis of breast cancer and its progression in order to design targeted, molecularly based therapies.Like other cancers, the genesis of ductal carcinoma in the breast is the result of unprogrammed genetic and epigenetic changes, which lead to mal-regulation of cellular growth.

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“…22 For this study, we chose Panc-1 and BxPC-3. Upregulation of snail and vimentin mRNA and protein expression, and downregulation of E-cadherin occurred in two different pancreatic cancer cell lines, Panc-1 and BxPC-3, compared with monocultured parental cells.…”

Section: Discussionmentioning

confidence: 99%

M2-polarized tumor-associated macrophages promoted epithelial–mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway

Liu

Shi

et al. 2013

Laboratory Investigation

381

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M2-polarized tumor-associated macrophages (TAMs) are key regulators of the link between inflammation and cancer. A negative correlation between infiltration intensity of M2-polarized TAMs and prognosis of pancreatic cancer has been reported. Epithelial-mesenchymal transition (EMT) is an important biological process in the progression of primary tumors toward metastasis. Inflammation-induced EMT has been previously shown, therefore, we hypothesized M2-polarized TAMs could induce EMT in pancreatic cancer. Toll-like receptor 4 (TLR4) signaling has an active role in tumor progression during chronic inflammation and the receptor is primarily expressed on macrophages. Activation of TLR4 on M2-polarized TAMs stimulates an increase in the cytokine interleukin-10 (IL-10); consequently, another aim was to investigate the potential role of TLR4/IL-10 signaling in the EMT of pancreatic cancer. Treatment with IL-4 (20 ng/ml) for 24 h successfully induced the polarization of macrophage cell line RAW 264.7 to M2 phenotype, IL-10 high , IL-12 low , and IL-23 low , and high expression of CD204 and CD206. A coculture system allowed investigation of the roles of M2-polarized TAMs and TLR4/IL-10 signaling in the EMT of Panc-1 and BxPC-3 pancreatic cancer cell lines. Our results showed that coculture with M2-polarized TAMs increased fibroblastic morphology, upregulated mesenchymal markers vimentin and snail at the mRNA and protein levels, and increased proliferation, migration, and metalloproteinase (MMP)2 and MMP9 proteolytic activity in pancreatic cancer cells. Simultaneously, coculture with M2-polarized TAMs decreased the expression of the epithelial marker E-cadherin. Coculture with pancreatic cancer cells increased TLR4 mRNA and protein expression in M2-polarized TAMs. Application of TLR4 siRNA and neutralizing antibodies against TLR4 and IL-10 markedly inhibited E-cadherin reduction and the upregulation of snail and vimentin. Furthermore, activation of TLR4 signaling by lipopolysaccharide profoundly increased the EMT of pancreatic cancer cells. In conclusion, M2-polarized TAMs promoted EMT in pancreatic cancer cells partially through TLR4/IL-10 signaling, suggesting novel therapeutic strategies and enhancing our understanding of M2-polarized TAMs. Pancreatic ductal adenocarcinoma is highly malignant and is resistant to chemo-and radiotherapeutics. 1 Recent evidence suggests the inflammatory environment of the tumor is critical for its progression. 2 Tumor-associated macrophages (TAMs) are derived from circulating monocytes, which are highly abundant within the tumor and provide a key link between inflammation and cancer. 3 TAMs develop a phenotype similar to M2-polarized macrophages and respond to recruitment to the tumor microenvironment. 4 Previous studies have commonly associated elevated numbers of TAMs with tumor progression and poor patient outcome. 5 This association is likely linked to the typical presence of M2-polarized TAMs during cancer invasion, 6 however, the exact mechanisms by which these cells influence the pr...

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Loss of WISP-2/CCN5 signaling in human pancreatic cancer: A potential mechanism for epithelial-mesenchymal-transition

Cited by 63 publications

References 32 publications

Gain of Oncogenic Function of p53 Mutants Induces Invasive Phenotypes in Human Breast Cancer Cells by Silencing CCN5/WISP-2

Gain of Oncogenic Function of p53 Mutants Induces Invasive Phenotypes in Human Breast Cancer Cells by Silencing CCN5/WISP-2

CCN5/WISP-2: A micromanager of breast cancer progression

M2-polarized tumor-associated macrophages promoted epithelial–mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway

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