Malignant pleural mesothelioma nodules remodel their surroundings to vascularize and grow

Our plain-English summary of Malignant pleural mesothelioma nodules remodel their surroundings to vascularize and grow, by I. Kovacs, E. Bugyik, K. Dezso, et al (Translational Lung Cancer Research, 2022).

The study

• Authors: I. Kovacs, E. Bugyik, K. Dezso, J. Tarnoki-Zach, E. Mehes, M. Gulyas, A. Czirok, E. Lang, M. Grusch, K. Schelch, B. Hegedus, I. Horvath, N. Barany, Z. Megyesfalvi, A. Tisza, Z. Lohinai, M.A. Hoda, K. Hoetzenecker, F. Pezzella, S. Paku, V. Laszlo, B. Dome
• Journal: Translational Lung Cancer Research
• Published: 2022;11(6):991-1008
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The microanatomical steps of malignant pleural mesothelioma (MPM) vascularization and the resistance mechanisms to anti-angiogenic drugs in MPM are unclear.

Methods: We investigated the vascularization of intrapleurally implanted human P31 and SPC111 MPM cells. We also assessed MPM cell's motility, invasion and interaction with endothelial cells in vitro.

Results: P31 cells exhibited significantly higher two-dimensional (2D) motility and three-dimensional (3D) invasion than SPC111 cells in vitro. In co-cultures of MPM and endothelial cells, P31 spheroids permitted endothelial sprouting (ES) with minimal spatial distortion, whereas SPC111 spheroids repealed endothelial sprouts. Both MPM lines induced the early onset of submesothelial microvascular plexuses covering large pleural areas including regions distant from tumor colonies. The development of these microvascular networks occurred due to both intussusceptive angiogenesis (IA) and ES and was accelerated by vascular endothelial growth factor A (VEGF-A)-overexpression. Notably, SPC111 colonies showed different behavior to P31 cells. P31 nodules incorporated tumor-induced capillary plexuses from the earliest stages of tumor formation. P31 cells deposited a collagenous matrix of human origin which provided "space" for further intratumoral angiogenesis. In contrast, SPC111 colonies pushed the capillary plexuses away and thus remained avascular for weeks. The key event in SPC111 vascularization was the development of a desmoplastic matrix of mouse origin. Continuously invaded by SPC111 cells, this matrix transformed into intratumoral connective tissue trunks, providing a route for ES from the diaphragm.

Conclusions: Here, we report two distinct growth patterns of orthotopically implanted human MPM xenografts. In the invasive pattern, MPM cells invade and thus co-opt peritumoral capillary plexuses. In the pushing/desmoplastic pattern, MPM cells induce a desmoplastic response within the underlying tissue which allows the ingrowth of a nutritive vasculature from the pleura.

2022 Translational Lung Cancer Research. All rights reserved.

In plain English

This was a laboratory study in mice combined with cell-culture experiments. The authors injected two human malignant pleural mesothelioma (MPM) cell lines, P31 (epithelioid) and SPC111 (biphasic), into the pleural cavity of SCID mice (53 mice for SPC111, 30 for P31, plus 18 for a VEGF-A-overexpressing SPC111 line) and examined the diaphragm by confocal and electron microscopy. Mice given SPC111 became moribund sooner than those given P31 (28-35 vs. 42-52 days). Both lines induced vascular plexuses on the diaphragm, including areas without tumour. P31 nodules took up the new vessels and became well vascularized, whereas SPC111 nodules pushed vessels away and stayed avascular for 2-4 weeks until a desmoplastic matrix of mouse origin formed at their base, allowing vessels to sprout in. Control SPC111-RFP cells secreted 1.97 pg/mL of VEGF-A and the VEGF-A-overexpressing SPC111-RFP-VEGF-A cells secreted 10,750.47 pg/mL, and the overexpressing cells produced faster plexus formation. In vitro, P31 cells were more motile and invasive, and SPC111 spheroids distorted endothelial sprouting more than P31 spheroids. The authors concluded that two distinct vascular growth patterns exist in these xenografts.

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: animal experiment (orthotopic human MPM xenografts in SCID mice) combined with in vitro cell-culture assays
• Who was studied: Male SCID mice: 53 for the SPC111 model, 30 injected with P31 cells, and 18 more for the SPC111-VEGF-A model; plus cultured human MPM cell lines (SPC111, biphasic; P31, epithelioid) and HUVEC endothelial cells
• Exposure: Not an asbestos-exposure study: mice received intrapleural injection of human MPM cells (2x10^6 SPC111 or 1x10^6 P31) between the 2nd and 3rd ribs; some SPC111 cells were retrovirally engineered to overexpress VEGF-A
• Main results:
  • Mice inoculated with SPC111 became moribund earlier than those inoculated with P31
  • Both cell lines induced vascular proliferations on the diaphragm, also in areas free of tumour colonies
  • SPC111 nodules displaced the vessels and remained avascular, while P31 nodules incorporated them and became well vascularized
  • SPC111 vascularization followed formation of a desmoplastic matrix at the tumour base, shown with species-specific antibodies to be of mouse origin
  • VEGF-A secretion was 1.97 pg/mL for control SPC111-RFP cells and 10,750.47 pg/mL for the VEGF-A-transduced SPC111-RFP-VEGF-A cells
  • VEGF-A overexpression accelerated plexus formation, covering the whole diaphragm and killing the mice by day 7 without macroscopic tumour colonies
  • In avascular SPC111 nodules, BrdU proliferation was lowest in the tumour area facing the lungs
  • In HUVEC co-cultures, SPC111 spheroids distorted endothelial sprout arbors more than P31 spheroids
  • P31 cells were more motile and invasive in vitro than SPC111 cells
  • Human COL1A1 mRNA expression was higher in P31 than in SPC111 cells
• The authors' conclusion: The authors concluded that MPM xenografts vascularized by two distinct patterns: an invasive pattern in which tumour cells co-opt peritumoral capillary plexuses, and a pushing/desmoplastic pattern in which a desmoplastic response in the underlying tissue permits endothelial ingrowth; they suggested this might relate to varying responses to anti-angiogenic agents.
• Limitations the authors state:
  • Human MPM growth may differ because the human diaphragm's anatomy differs from the mouse diaphragm
  • Use of cell lines and immune-deficient mice means the immunological context of tumorigenesis cannot be fully reproduced; results need validation in other models
  • Early death of the VEGF-A-overexpressing group prevented assessment of how VEGF-A levels affect the resulting vascularization patterns
  • Whether the described vascular growth patterns correlate with the histological origin of the tumour cells remains unclear

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Angiogenesis, Desmoplastic Mesothelioma, Diaphragm, Pleura.

Related studies

• Multicellular contractility contributes to the emergence of mesothelioma nodules — J. Tarnoki-Zach, P. Stockhammer, et al. (2020)
• Laser ablation-inductively coupled plasma-mass spectrometry analysis reveals differences in chemotherapeutic drug distribution in surgically resected pleural mesothelioma — A. Tisza, T. Klikovits, et al. (2023)
• FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal — K. Schelch, C. Wagner, et al. (2018)
• Prognostic impact of PD-1 and PD-L1 expression in malignant pleural mesothelioma: an international multicenter study — L. Brcic, T. Klikovits, et al. (2021)
• Circulating FGF18 is decreased in pleural mesothelioma but not correlated with disease prognosis — B. Mosleh, K. Schelch, et al. (2023)
• Characterization of human malignant mesothelioma cell lines orthotopically implanted in the pleural cavity of immunodeficient mice for their ability to grow and form metastasis — D. Martarelli, A. Catalano, et al. (2006)

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