PTHrP promotes colon cancer cell migration and invasion in an integrin α6β4-dependent manner through activation of Rac1

Mula, Ramanjaneya V.R.; Bhatia, Vandanajay; Falzon, Miriam

doi:10.1016/j.canlet.2010.06.009

Cited by 23 publications

(10 citation statements)

References 52 publications

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“…Indeed, the ability of PTHrP to regulate mammary bud development through paracrine interactions with the mesenchyme is established (Hens and Wysolmerski, 2005), but the ability of a specific integrin to control this paracrine mechanism is novel. Interestingly, it was reported previously that PTHrP can regulate β4 expression based on in vitro data (Mula et al, 2010; Shen et al, 2007), a result contrary to our finding. It may be possible, however, that a feedback loop exists between β4 and PTHrP.…”

Section: Resultscontrasting

confidence: 99%

Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

Sun

Feltri³

et al. 2015

Developmental Biology

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The integrin α6β4 (referred to as β4) is expressed in epithelial cells where it functions as a laminin receptor. Although in vitro studies have implicated β4 in the biology of mammary epithelial cells, its contribution to mammary gland development has not been settled. To address this problem, we generated and analyzed itgb4flox/flox MMTV-Cre− and itgb4flox/flox MMTV-Cre+ mice. The salient features of embryonic mammary tissue from itgb4flox/flox MMTV-Cre+ mice were significantly smaller mammary buds and increased apoptosis in the surrounding mesenchyme. Also, compared to control glands, the itgb4-deleted mammary buds lacked expression of the progenitor cell marker CK14 and they were unable to generate mammary glands upon transplantation into cleared fat pads of recipient mice. Analysis of mammary glands at puberty and during pregnancy revealed that itgb4-diminished mammary tissue was unable to elongate and undergo branching morphogenesis. Micro-dissection of epithelial cells in the mammary bud and of the surrounding mesenchyme revealed that loss of β4 resulted in a significant decrease in the expression of parathyroid hormone related protein (PTHrP) in epithelial cells and of target genes of the PTHrP receptor in mesenchymal cells. Given that the phenotype of the itgb4-deleted mammary tissue mimicked that of the PTHrP knockout, we hypothesized that β4 contributes to mammary gland development by sustaining PTHrP expression and enabling PTHrP signaling. Indeed, the inability of itgb4-deleted mammary buds to elongate was rescued by exogenous PTHrP. These data implicate a critical role for the β4 integrin in mammary gland development and provide a mechanism for this role.

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Section: Resultscontrasting

confidence: 99%

Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

Sun

Feltri³

et al. 2015

Developmental Biology

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“…Mesenchymal-type migration in melanoma cells is driven by NEDD9 (a metastasis-related gene) and DOCK3 (a RAC GEF) through the modulation of RAC1 activity(35). PTHrP (parathyroid hormone-related peptide)-stimulated cell migration and invasion in colorectal adenocarcinomas is dependent on RAC1 activity, which is augmented by the increased expression of α6β4 integrin and TIAM1 these cells exhibit(36). …”

Section: Rac1 and Metastasismentioning

confidence: 99%

RAC1: An Emerging Therapeutic Option for Targeting Cancer Angiogenesis and Metastasis

Bid

Roberts

Manchanda

et al. 2013

Molecular Cancer Therapeutics

227

205

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Angiogenesis and metastasis are well recognized as processes fundamental to the development of malignancy. Both processes involve the coordination of multiple cellular and chemical activities through myriad signaling networks, providing a mass of potential targets for therapeutic intervention. This review will focus on one master regulator of cell motility, RAC1, and the existing data with regard to its role in cell motility, including particular roles for tumor angiogenesis and invasion/metastasis. We also emphasize the pre-clinical investigations carried out with RAC1 inhibitors to evaluate the therapeutic potential of this target. Herein we explore potential future directions as well as the challenges of targeting RAC1 in the treatment of cancer. Recent insights at the molecular and cellular levels are paving the way for a more directed and detailed approach to target mechanisms of RAC1 regulating angiogenesis and metastasis. Understanding these mechanisms may provide insight into RAC1 signaling components as alternative therapeutic targets for tumor angiogenesis and metastasis.

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“…Moreover, PTHrP significantly increased LoVo cell anchorage-independent growth in soft agar via its intracrine pathway and nuclear action, and also induced xenograft growth in nude mice, thereby confirming its transformation potential also in in vivo models. More recently, up-regulation of integrin α6β4 by PTHrP was proven to promote the migratory and invasive effect through activation of the Rho GTPase Rac1, known to play a role in cell motility [48], via the switching-on of the phosphatidylinositol 3-kinase/Akt pathway with the consequent activation of the Rac-specific guanine nucleotide exchange factor Tiam1 [49-52]. By consequence, targeting PTHrP expression and/or intracrine signaling might be a useful tool for the control of colon tumor cell growth, migration, and invasion.…”

Section: Pthrp As a Stimulator Of Cell Survival And Proliferation Of mentioning

confidence: 99%

Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications

Luparello

2011

Cancers

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Parathyroid hormone-related protein (PTHrP), classically regarded as the mediator of the humoral hypercalcemia of malignancy syndrome, is a polyhormone that undergoes proteolytic processing into smaller bioactive forms. These bioactive forms comprise an N-terminal-as well as midregion-and C-terminal peptides, which have been shown to regulate various biological events, such as survival, proliferation and differentiation, in diverse cell model systems, both normal and pathological. A number of experimental data have demonstrated that PTHrP is also able to modulate tumor-relevant phenotypic expressions, thereby playing a role in early and advanced tumorigenesis, and in the response to treatment. In particular, interest has mainly been focused on the effects of PTHrP on cell proliferation/apoptosis, migration and invasion, which are the main roles involved in cancer development in vivo. The objective of this review is to discuss collectively the literature data on the molecular and biochemical basis of the mechanisms underlying the different, and sometimes opposite, effects exerted by PTHrP on various neoplastic cytotypes, with some final comments on both present and potential utilization of PTHrP as a target for anti-cancer therapy.

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PTHrP promotes colon cancer cell migration and invasion in an integrin α6β4-dependent manner through activation of Rac1

Cited by 23 publications

References 52 publications

Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

RAC1: An Emerging Therapeutic Option for Targeting Cancer Angiogenesis and Metastasis

Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications

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