Multipotent cancer stem cells derived from human malignant peritoneal mesothelioma promote tumorigenesis

Our plain-English summary of Multipotent cancer stem cells derived from human malignant peritoneal mesothelioma promote tumorigenesis, by S. Varghese, R. Whipple, S.S. Martin, et al (PloS One, 2012).

The study

• Authors: S. Varghese, R. Whipple, S.S. Martin, H.R. Alexander
• Journal: PloS One
• Published: 2012;7(12):e52825
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

During the progression of malignant peritoneal mesothelioma (MPeM), tumor nodules propagate diffusely within the abdomen and tumors are characterized by distinct phenotypic sub-types. Recent studies in solid organ cancers have shown that cancer stem cells (CSCs) play a pivotal role in the initiation and progression of tumors. However, it is not known whether tumorigenic stem cells exist and whether they promote tumor growth in MPeM. In this study, we developed and characterized a CSC model for MPeM using stably expandable tumorigenic stem cells derived from patient tumors. We found morphologically distinct populations of CSCs that divide asymmetrically or symmetrically in MPeM in vitro cell culture. The MPeM stem cells (MPeMSCs) express stem cell markers c-MYC, NES and VEGFR2 and in the presence of matrix components cells form colony spheres. MPeMSCs are multipotent, differentiate into neuronal, vascular and adipose progeny upon defined induction and the differentiating cells express lineage-specific markers such as TUBB3, an early neuronal marker; vWF, VEGFA, VEGFC and IL-8, endothelial markers; and PPARγ and FABP4, adipose markers. Xenotransplantation experiments using MPeMSCs demonstrated early tumor growth compared with parental cells. Limiting dilution experiments using MPeMSCs and endothelial lineage-induced cells derived from a single MPeMSC resulted in early tumor growth in the latter group indicating that endothelial differentiation of MPeMSCs is important for MPeM tumor initiation. Our observation that the MPeM tumors contain stem cells with tumorigenic potential has important implications for understanding the cells of origin and tumor progression in MPeM and hence targeting CSCs may be a useful strategy to inhibit malignant progression.

In plain English

This laboratory study used cell lines from human malignant peritoneal mesothelioma (cancer of the abdominal lining), along with mouse experiments. It did not study asbestos or any other exposure. The authors used Meso-CL1, which formed tumors in immunocompromised mice. From it they collected floating cells identified as cancer stem cells. These cells divided both unequally and equally. They expressed the mesothelioma marker MSLN, with significantly higher c-MYC than parent cells. Under specific conditions they developed nerve-like, blood-vessel-lining and fat-cell features. Under the skin of mice (8 per group), parent cells produced a first palpable tumor on day 30, and stem cells on day 15. Next, cells from one stem cell were split: some were grown on Matrigel, a matrix gel, to induce blood-vessel-lining differentiation, and others were kept undifferentiated with LIF. Five hundred Matrigel-grown cells injected in Matrigel (8 mice) produced tumors first felt on day 59. Five hundred of the others, injected in a salt solution, PBS (10 mice), produced none within two months. The authors concluded that the cells' ability to become several cell types may contribute to tumor growth in patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell-culture study with mouse xenograft (tumor transplantation) experiments
• Who was studied: Three cell lines (Meso-CL1, Meso-CL2, Meso-CL3) derived from human malignant peritoneal mesothelioma tumors collected under National Cancer Institute protocols. Meso-CL1 was used for the study. Mouse experiments used female athymic nude mice aged 4 to 5 weeks. The number of patients and the dates and locations of tumor collection are not given.
• Exposure: No asbestos or other fiber exposure was studied. The experiments involved growing tumor-derived cells under different culture conditions and injecting them into mice.
• Main results:
  • The isolated stem cells divided both asymmetrically (into two unequal cells) and symmetrically (into two identical cells).
  • Both the stem cells and the parental mesothelioma cells strongly expressed the mesothelioma marker MSLN (mesothelin).
  • c-MYC expression was significantly higher in the stem cells than in the parental cells. Other stem cell markers showed a similar pattern in both groups.
  • The markers CD133, CD31 and CD144 were undetectable in the stem cells.
  • Under neuronal culture conditions, the stem cells became neuron-like cells expressing NES and TUBB3.
  • On Matrigel, the stem cells formed tubular networks. IL-8 showed a 10-fold increase during this endothelial (blood-vessel-lining) differentiation, compared with the undifferentiated stem cells.
  • Under adipose culture conditions, cells accumulated lipid deposits and showed significant upregulation of the fat-cell markers PPARγ and FABP4.
  • In mice injected under the skin, the first palpable tumor appeared on day 30 with parental cells (n = 8) and on day 15 with stem cells (n = 8).
  • Neural lineage-induced cells produced a first palpable tumor on day 35.
  • In limiting dilution experiments, cells derived from a single stem cell were split. One portion was grown on Matrigel to induce endothelial differentiation, and the other was grown in regular culture with LIF.
  • Five hundred of the Matrigel-grown cells, injected in Matrigel (n = 8), produced tumors first palpated on day 59. The same number of LIF-grown stem cells, injected in PBS (n = 10), did not grow tumors during a two-month period.
  • Early tumors grown from endothelial lineage-induced cells expressed the neuronal markers NES and TUBB3.
• The authors' conclusion: The authors concluded that malignant peritoneal mesothelioma contains cancer stem cells, and that the ability of these cells to become several cell types and to change form may be a contributing factor in tumor growth in patients.
• Limitations the authors state:
  • The authors stated that the significance of the encapsulated (capsular) stem cells needs further investigation.
  • Time-lapse imaging could not be done on the floating encapsulated cells, so their division pattern was inferred from light and fluorescent microscopy.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: STEM, Peritoneal Mesothelioma, Tumorigenesis.

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