Targeting the β-catenin/TCF transcriptional complex in the treatment of multiple myeloma

Sukhdeo, Kumar; Mani, Mala; Zhang, Yunyu; Dutta, Jui; Yasui, Hiroshi; Rooney, Melissa; Carrasco, Daniel E.; Ma, Zheng; He, Hongchao; Tai, Yu-Tzu; Mitsiades, Constantine S.; Anderson, Kenneth C.; Carrasco, Daniel R.

doi:10.1073/pnas.0610299104

Cited by 200 publications

(223 citation statements)

References 39 publications

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“…In the case of human colon carcinomas, activating mutations have been described (Kinzler and Vogelstein, 1996). However, in multiple myeloma and other hematologic malignancies, no mutations have been identified in the Wnt/b-catenin pathway, indicating alternative mechanisms for b-catenin activation (Derksen et al, 2004;Qiang et al, 2005;Sukhdeo et al, 2007). Interestingly CYLD expression is downregulated in multiple myeloma (Annunziata et al, 2007), suggesting that similarly to our model, reduced CYLD activity could cause activation of b-catenin in this type of cancer.…”

Section: Discussionsupporting

confidence: 54%

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

et al. 2010

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In this study, we demonstrate that the expression in tumorigenic epidermal cells of a catalytically inactive form of CYLD (CYLD C/S ) that mimics the identified mutations of cyld in human tumors and competes with the endogenous CYLD results in enhanced cell proliferation and inhibition of apoptosis; it also stimulates cell migration and induces the expression of angiogenic factors, including vascular endothelial growth factor-A. Altogether, these characteristics indicate an increased oncogenicity of the tumorigenic epidermal CYLD C/S mutant cells in vitro. Moreover, we show the increase in malignancy of epidermal squamous cell carcinomas that express the CYLD C/S transgene in an in vivo xenograft model. Tumors carrying the mutated CYLD C/S exhibit a fast growth, are poorly differentiated and present a robust angiogenesis. CYLD C/S tumors are also characterized by their elevated proliferation rate and decreased apoptosis. In contrast with previous studies showing the development of benign tumors by mutations in the CYLD gene, here we provide evidence that the occurrence of mutations in the CYLD gene in tumorigenic epidermal cells (carrying previous mutations) increases the aggressiveness of carcinomas, mainly through enhancement of the expression of angiogenic factors, having therefore a key role in epidermal cancer malignancy.

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Section: Discussionsupporting

confidence: 54%

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

et al. 2010

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“…In a total of 252 genes related to stem cells, apoptosis and signaling pathway, we found the downregulation of Dkk1, Wnt11 and b-catenin genes that have a crucial role in the regulation of cancer stem cells including MM cells (Supplementary Table 3). 16,19,32 When we examined the expression of b-catenin at protein levels, active b-catenin localized in the nucleus as a speckled pattern, but after treatment with C3B3 the amount of active b-catenin markedly decreased in the nucleus (Figure 5b). …”

Section: Rpmi8226mentioning

confidence: 99%

“…Specifically, b-catenin, a key regulator of Wnt pathway is illegitimately activated in MM cells. 16,19 However, the role of Wnt/ b-catenin pathway for MM cancer stem cells remains unknown. On the other hand, the Oct4/Sox2/Nanog pluripotency axis has consistently been reiterated as the central pathway of pluripotency and self-renewal in embryonic stem cells.…”

Section: Introductionmentioning

confidence: 99%

Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors

et al. 2012

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“…A phase 2 clinical trial (NCT00896532) is currently evaluating AMG785 in osteoporotic post-menopausal women in comparison to placebo, alendronate and teriparatide. No studies in tumorinduced bone disease have been opened until now, due to concerns regarding potential tumorigenic effects, since tumor cell growth may be stimulated by WNT signaling [100]. Further studies to exclude any stimulatory effects on tumor growth are required for all anabolic agents acting on the WNT/β-catenin pathway.…”

Section: Treatment Of MM Bone Disease With Bone-anabolic Agentsmentioning

confidence: 99%

Bone Anabolic Agents for the Treatment of Multiple Myeloma

Vallet

2011

Cancer Microenvironment

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The majority of patients with multiple myeloma develop bone osteolytic lesions, which may lead to severe complications, including pain and fractures. The pathogenesis of bone disease depends on uncoupled bone remodeling, characterized by increased bone resorption due to upregulation of osteoclast activity and decreased bone formation due to osteoblast inhibition. In myeloma, impaired osteoblast differentiation and increased apoptosis have been described. Responsible for these effects are integrin-mediated adhesion to tumor cells and soluble factors, including WNT antagonists, BMP2 inhibitors and numerous cytokines. Based on the evidence of osteoblast suppression in myeloma, bone anabolic agents have been developed and are currently undergoing clinical evaluation. Due to bidirectional inhibitory effects characterizing tumor cells and osteoblasts interactions, agents targeting osteoblasts are expected to reduce tumor burden along with improvement of bone health. This review summarizes the current knowledge on osteoblast inhibition in myeloma and provides an overview on the clinical grade agents with bone anabolic properties, which represent new promising therapeutic strategies in myeloma.

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Targeting the β-catenin/TCF transcriptional complex in the treatment of multiple myeloma

Cited by 200 publications

References 39 publications

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors

Bone Anabolic Agents for the Treatment of Multiple Myeloma

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