Gefitinib inhibits the cross‐talk between mesenchymal stem cells and prostate cancer cells leading to tumor cell proliferation and inhibition of docetaxel activity

Borghese, Cinzia; Cattaruzza, Lara; Pivetta, Eliana; Normanno, Nicola; Luca, Antonella De; Mazzucato, M.; Celegato, Marta; Colombatti, Alfonso; Aldinucci, Donatella

doi:10.1002/jcb.24456

Cited by 35 publications

(36 citation statements)

References 47 publications

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“…Recently, we found that CM from MSCs and especially from TE-MSCS increased PC3 cell colony growth [5]. Our data, showing that MSCs-CM from NZ and ZA treated cells resulted less active in increasing the clonogenic growth of PC3 cells, suggested that ZA and especially NZ may decrease the protumorigenic effects of MSCs.…”

Section: Discussionmentioning

confidence: 62%

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Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells

et al. 2017

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Zoledronic Acid (ZA) rapidly concentrates into the bone and reduces skeletal-related events and pain in bone metastatic prostate cancer (PCa), but exerts only a limited or absent impact as anti-cancer activity. Recently, we developed self-assembling nanoparticles (NPS) encapsulating zoledronic acid (NZ) that allowed a higher intratumor delivery of the drug compared with free zoledronic acid (ZA) in in vivo cancer models of PCa. Increasing evidence suggests that Bone Marrow (BM) Mesenchymal stromal cells (BM-MSCs) are recruited into the stroma of developing tumors where they contribute to progression by enhancing tumor growth and metastasis.We demonstrated that treatment with NZ decreased migration and differentiation into adipocytes and osteoblasts of MSCs and inhibited osteoclastogenesis. Treatment with NZ reduced the capability of MSCs to promote the migration and the clonogenic growth of the prostate cancer cell lines PC3 and DU145. The levels of Interleukin-6 and of the pro-angiogenic factors VEGF and FGF-2 were significantly reduced in MSC-CM derived from MSCs treated with NZ, and CCL5 secretion was almost totally abolished. Moreover, treatment of MSCs with supernatants from PC3 cells, leading to tumor-educated MSCs (TE-MSCs), increased the secretion of IL-6, CCL5, VEGF and FGF-2 by MSCs and increased their capability to increase PC3 cells clonogenic growth. Treatment with NZ decreased cytokine secretion and the pro-tumorigenic effects also of TE-MSCS. In conclusion, demonstrating that NZ is capable to inhibit the cross talk between MSCs and PCa, this study provides a novel insight to explain the powerful anticancer activity of NZ on PCa.

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Section: Discussionmentioning

confidence: 62%

“…We have previously demonstrated that MSCs-CM increased the clonogenic growth of PCa cells [5]. Thus, we evaluated the effects of NZ as well as free ZA on the ability of MSCs-CM to support the clonogenic growth of prostate cancer cells (Figure 5).…”

Section: Resultsmentioning

confidence: 99%

Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells

et al. 2017

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“…7). CCL5 has also been identified as a MSC-derived metastasis promoting factor [63]. Secretion of CCL5 from MSC is highly associated with both the physiologic and pathologic features of metastasis.…”

Section: Discussionmentioning

confidence: 99%

The Role of CCL5 in the Ability of Adipose Tissue-Derived Mesenchymal Stem Cells to Support Repair of Ischemic Regions

Kimura

Nagano

Salazar

et al. 2014

Stem Cells and Development

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Mesenchymal stem cells (MSC) are multipotent and possess high proliferative activity, and thus are thought to be a reliable cell source for cell therapies. Here, we isolated MSC from adult tissues-bone marrow (BM-MSC), dental tissue (DT-MSC), and adipose tissue (AT-MSC)-to compare how autotransplantation of these MSC effectively supports the repair of bone fracture and ischemic tissue. An analysis by in vitro differentiation assays showed no significant difference among these MSC. The degree of calcification at the joint region of bone fracture was higher in mice transplanted with AT-MSC than in mice transplanted with BM-MSC or DT-MSC. To compare the abilities of MSC, characterize how those MSC affect the repair of ischemic tissue, vascular occlusion was performed by ligation of the femoral artery and vein. Of note, the blood flow in the ischemic region rapidly increased in mice injected with AT-MSC, as contrasted with mice injected with BM-or DT-MSC. The number of CD45-and F4/80-positive cells at the femoral region was higher in AT-MSC recipients than in recipients of BM-MSC or DT-MSC. We evaluated the mRNA expression of angiogenic and migration factors in MSC and found the expression of CCL5 mRNA was higher in AT-MSC than in BM-MSC or DT-MSC. Transplantation of AT-MSC with impaired expression of CCL5 clearly showed a significant delay in the recovery of blood flow compared with the control. These findings have fundamental implications for the modulation of AT-MSC in the repair of vasculature and bone fracture.

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“…In a subsequent study, the same research group investigated a cross-talk existing between prostate cancer cell line (PC3 cells) and MSCs and demonstrated again that some physiological functions depending on the EGF-activation of MSCs (i.e. CCL5 secretion) might be inhibited by gefitinib [189]. Contemporaneously, Liu et al .…”

Section: Msc and Tk Inhibitorsmentioning

confidence: 99%

Tyrosine kinase inhibitors and mesenchymal stromal cells: effects on self-renewal, commitment and functions

et al. 2016

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The hope of selectively targeting cancer cells by therapy and eradicating definitively malignancies is based on the identification of pathways or metabolisms that clearly distinguish “normal” from “transformed” phenotypes. Some tyrosine kinase activities, specifically unregulated and potently activated in malignant cells, might represent important targets of therapy. Consequently, tyrosine kinase inhibitors (TKIs) might be thought as the “vanguard” of molecularly targeted therapy for human neoplasias. Imatinib and the successive generations of inhibitors of Bcr-Abl1 kinase, represent the major successful examples of TKI use in cancer treatment. Other tyrosine kinases have been selected as targets of therapy, but the efficacy of their inhibition, although evident, is less definite. Two major negative effects exist in this therapeutic strategy and are linked to the specificity of the drugs and to the role of the targeted kinase in non-malignant cells. In this review, we will discuss the data available on the TKIs effects on the metabolism and functions of mesenchymal stromal cells (MSCs). MSCs are widely distributed in human tissues and play key physiological roles; nevertheless, they might be responsible for important pathologies. At present, bone marrow (BM) MSCs have been studied in greater detail, for both embryological origins and functions. The available data are evocative of an unexpected degree of complexity and heterogeneity of BM-MSCs. It is conceivable that this grade of intricacy occurs also in MSCs of other organs. Therefore, in perspective, the negative effects of TKIs on MSCs might represent a critical problem in long-term cancer therapies based on such inhibitors.

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Gefitinib inhibits the cross‐talk between mesenchymal stem cells and prostate cancer cells leading to tumor cell proliferation and inhibition of docetaxel activity

Cited by 35 publications

References 47 publications

Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells

Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells

The Role of CCL5 in the Ability of Adipose Tissue-Derived Mesenchymal Stem Cells to Support Repair of Ischemic Regions

Tyrosine kinase inhibitors and mesenchymal stromal cells: effects on self-renewal, commitment and functions

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