Human ovarian carcinoma–associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production

McLean, Karen; Gong, Yusong; Choi, Yun‐Jung; Deng, Ning; Yang, Kun; Bai, Shoumei; Cabrera, Lourdes; Keller, Evan T.; McCauley, Laurie K.; Cho, Kathleen R.; Buckanovich, Ronald J.

doi:10.1172/jci45273

Cited by 327 publications

(361 citation statements)

References 56 publications

Supporting

Mentioning

339

Contrasting

Unclassified

Order By: Relevance

“…S10), which corroborates this hypothesis and presents LOX-elicited signaling as a prominent molecular feature of this transient state. Because the protumorigenic and prometastatic functions of stromal MSCs have now been recognized in multiple tumor settings (7,38), it would be important to exploit such a platform to further characterize the molecular nature of the heterotypic crosstalk that takes place at the tumor to stroma interface.…”

Section: Discussionmentioning

confidence: 99%

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

El-Haibi

Bell

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

199

161

View full text Add to dashboard Cite

Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the ability to differentiate into multiple mesoderm lineages in the course of normal tissue homeostasis or during injury. We have previously shown that MSCs migrate to sites of tumorigenesis, where they become activated by cancer cells to promote metastasis. However, the molecular and phenotypic attributes of the MSCinduced metastatic state of the cancer cells remained undetermined. Here, we show that bone marrow-derived human MSCs promote de novo production of lysyl oxidase (LOX) from human breast carcinoma cells, which is sufficient to enhance the metastasis of otherwise weakly metastatic cancer cells to the lungs and bones. We also show that LOX is an essential component of the CD44-Twist signaling axis, in which extracellular hyaluronan causes nuclear translocation of CD44 in the cancer cells, thus triggering LOX transcription by associating with its promoter. Processed and enzymatically active LOX, in turn, stimulates Twist transcription, which mediates the MSC-triggered epithelial-to-mesenchymal transition (EMT) of carcinoma cells. Surprisingly, although induction of EMT in breast cancer cells has been tightly associated with the generation of cancer stem cells, we find that LOX, despite being critical for EMT, does not contribute to the ability of MSCs to promote the formation of cancer stem cells in the carcinoma cell populations. Collectively, our studies highlight a critical role for LOX in cancer metastasis and indicate that the signaling pathways controlling stroma-induced EMT are distinct from pathways regulating the development of cancer stem cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

El-Haibi

Bell

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

199

161

View full text Add to dashboard Cite

show abstract

“…In addition, MSC-derived CAFs produced soluble protumorigenic factors, including IL-6, which enhanced tumor growth and proliferation (54). Combining cancer-associated MSCs with tumor cells in vivo and in vitro has been shown to result in increased expression of the bone morphogenetic protein (BMP) signaling network, which has several pathologic roles in cancer progression (55). To determine the phenotypic changes that are orchestrated during MSC-to-myofibroblast differentiation, Cho and colleagues treated adipose tissuederived MSCs with exosomes isolated from 2 ovarian cancer cell lines, OVCAR-3 and SKOV-3 (56).…”

Section: Mesenchymal Stem Cellsmentioning

confidence: 99%

Revisiting the Complexity of the Ovarian Cancer Microenvironment—Clinical Implications for Treatment Strategies

Musrap

Diamandis

2012

Molecular Cancer Research

View full text Add to dashboard Cite

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies in North American women. Given that EOC encompasses a broad class of tumors consisting of a variety of different histologic and molecular subtypes, which generates genetically and etiologically distinct tumors, several challenges arise during treatment of patients with this disease. Overlaying this complexity is the contribution of supporting cells, particularly stromal components such as fibroblasts and immune infiltrates that collectively create a microenvironment that promotes and enhances cancer progression. A notable example is the induction of angiogenesis, which occurs through the secretion of pro-angiogenic factors by both tumor and tumor-associated cells. The recent development of angiogenic inhibitors targeting tumor vasculature, which have been shown to improve patient outcome when combined with standard therapy, has launched a paradigm shift on how cancer patients should be treated. It is evident that future clinical practices will focus on the incorporation of therapies that antagonize the protumoral effects of such microenvironment contributors. Herein, an overview of the varying tumor-host interactions that influence tumor behavior will be discussed, in addition to the recent efforts undertaken to target these interactions and their potential to revolutionize EOC patient care.

show abstract

“…So far they have only been studied in relation to human ovarian cancer; McLean et al [20] discovered the presence of ovarian cancer-associated MSCs, which promoted tumor growth and increased the number of cancer stem cells. For this reason, and based on our previous study [21] confirming that a small proportion of cells were positive for a set of MSCs markers in ovarian cell cultures, we decided to explore MSCs from healthy human adult ovaries (indicated as PO-MSCs) and characterize them according to today's interpretation of MSCs, as well as compare them with other types of cells of mesodermal origin: bone marrow-derived MSCs and human adult dermal fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Putative mesenchymal stem cells isolated from adult human ovaries

Štimpfel

Cerkovnik

Novaković

et al. 2014

J Assist Reprod Genet

View full text Add to dashboard Cite

Purpose The purpose of this study was to show that healthy adult human ovaries can be a source of cells showing typical MSCs characteristics under in vitro conditions. Methods and results The cells, which were isolated from ovarian cortex tissue and named putative ovarian mesenchymal stem cells (PO-MSCs), were compared to bone marrowderived MSCs (BM-MSCs) and to adult human dermal fibroblasts (HDFs). The results of a gene expression analysis using the Human Mesenchymal Stem Cell RT² Profiler™ PCR Array revealed that PO-MSCs were different than fibroblasts. They expressed most of the analyzed genes as BM-MSCs, although some genes were differentially expressed. However, the heterogeneity of PO-MSCs samples was revealed. The PO-MSCs expressed the characteristic genes related to MSCs, such as CD105, CD44, CD90, M-CAM, CD73 and VCAM1. In addition, the expression of markers CD44, CD90, M-CAM and STRO-1 was confirmed in PO-MSCs using immunocytochemistry. The PO-MSCs showed multipotent character, since they were able to differentiate into the cells of adipogenic, osteogenic, neural and pancreatic lineage. Conclusions Healthy adult human ovaries can harbour an interesting population of cells showing typical MSCs characteristics under in vitro conditions and for this reason we named these cells putative MSCs. These cells express genes encoding main MSCs markers and have an interesting differential potential. Based on these results, we propose PO-MSCs as a novel type of MSCs which share some similarities with BMMSCs. Nevertheless they show distinct and specific characteristics and are not fibroblasts.

show abstract

Human ovarian carcinoma–associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production

Cited by 327 publications

References 56 publications

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

Revisiting the Complexity of the Ovarian Cancer Microenvironment—Clinical Implications for Treatment Strategies

Putative mesenchymal stem cells isolated from adult human ovaries

Contact Info

Product

Resources

About