The plexin-A1 receptor activates vascular endothelial growth factor-receptor 2 and nuclear factor-kappaB to mediate survival and anchorage-independent growth of malignant mesothelioma cells

Our plain-English summary of The plexin-A1 receptor activates vascular endothelial growth factor-receptor 2 and nuclear factor-kappaB to mediate survival and anchorage-independent growth of malignant mesothelioma cells, by A. Catalano, R. Lazzarini, S. Di Nuzzo, et al (Cancer Research, 2009).

The study

• Authors: A. Catalano, R. Lazzarini, S. Di Nuzzo, S. Orciari, A. Procopio
• Journal: Cancer Research
• Published: 2009;69(4):1485-93
• Cited by: 43 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The semaphorins and their receptors, the neuropilins and the plexins, are constituents of a complex regulatory system that controls axonal guidance. Moreover, many types of tumor cells express various members of semaphorins and receptors, but the biological activities within tumor mass and the signal transduction mechanism(s) they use are largely unknown. Here, we show that in asbestos-related malignant pleural mesothelioma (MPM), Semaphorin-6D (Sema6D) and its receptor plexin-A1 are frequently expressed and trigger a prosurvival program that promotes anchorage-independent growth of MPM cells. Interestingly, the same response is also controlled by the tyrosine kinase receptors of vascular endothelial growth factor (VEGF) through a nuclear factor-kappaB (NF-kappaB)-dependent pathway. We found that in MPM cells, plexin-A1 and VEGF-receptor 2 (VEGF-R2) are associated in a complex. Moreover, the presence of Sema6D promotes the tyrosine phosphorylation of VEGF-R2 in a plexin-A1-dependent manner. This is necessary for basal and Sema6D-induced NF-kappaB transcriptional activity, and NF-kappaB mediates tumor cell survival. Expression of Sema6D and plexin-A1 is induced by asbestos fibers and overexpression of plexin-A1 in nonmalignant mesothelial cells inhibits cell death after asbestos exposure. This work identifies a new biological function of semaphorins in cancer cells and suggests the involvement of an undescribed survival pathway during MPM tumorigenesis.

In plain English

This laboratory study examined how a receptor, plexin-A1, and a molecule acting on it, Semaphorin-6D (Sema6D), affect survival of malignant pleural mesothelioma cells. The authors used mesothelioma cell lines, nonmalignant met-5A mesothelial cells, three primary mesothelial cultures and 29 mesothelioma tissue specimens. In mesothelioma cells, switching off plexin-A1 and a related receptor, neuropilin-1, led to cell death. Cells carrying a shortened plexin-A1 failed to grow colonies in soft agar. In the 29 tumors, plexin-A1 and Sema6D staining were significantly correlated (16 positive for both; P = 0.02). Sema6D increased activation of a growth-factor receptor, VEGF-R2, in a plexin-A1-dependent way. This was needed for activity of NF-kappaB, a protein that switches genes on, which the authors reported mediates tumor cell survival. Crocidolite asbestos fibers strongly raised plexin-A1 and Sema6D in met-5A cells and primary mesothelial cultures. Met-5A cells given Sema6D, or engineered to make extra plexin-A1, were more resistant to being killed by crocidolite. The authors concluded that a plexin-A1-dependent pathway is critical for mesothelioma cell survival and anchorage-independent growth (colony growth without attachment to a surface). They said the exact mechanism remains unclear.

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) study of human mesothelial and mesothelioma cells, with immunohistochemical staining of human tissue specimens
• Who was studied: Human mesothelioma cell lines (H2052, H28, H2452, Ist-mes1), nonmalignant met-5A mesothelial cells and three primary mesothelial cultures established from patients. Also 38 tissue specimens diagnosed between 1999 and 2006: 29 malignant pleural mesotheliomas (19 epithelioid, 3 sarcomatous, 7 biphasic) and 9 non-neoplastic pleural tissues. Asbestos exposure was known in 23 of the mesothelioma cases, 2 had no history of exposure, and 4 had no data. The authors worked in Ancona, Italy; where the patients came from is not stated.
• Exposure: Crocidolite fibers applied to cultured cells: continuous exposure at 5 micrograms per square centimetre for the time-course tests, and 3 micrograms per square centimetre in the cell-death tests. Other lab treatments included gene silencing (siRNA) of plexin-A1, Sema6D, neuropilin-1 and VEGF-R2, Sema6D-enriched medium, VEGF, and the inhibitors SU5416 and BAY 11-7082.
• Main results:
  • In H2052 mesothelioma cells, knocking down both neuropilin-1 and plexin-A1 caused cell death; knocking down neuropilin-1 alone caused cell death in nonmalignant met-5A cells but not in H2052 cells. Similar results were seen in H28, H2452 and Ist-mes1 cells.
  • H2052 cells expressing a tailless (shortened) plexin-A1 failed to form colonies in soft agar.
  • Knocking down Sema6D together with neuropilin-1 caused death of H2052 cells; this was confirmed in H28 cells.
  • In the 29 mesothelioma tissue specimens, plexin-A1 and Sema6D staining were significantly correlated: 16 specimens (55.2%) were positive for both, with P = 0.02.
  • Sema6D promoted tyrosine phosphorylation (activation) of VEGF-R2 in a plexin-A1-dependent manner. According to the authors, this was necessary for NF-kappaB transcriptional activity, both basal and Sema6D-induced, and NF-kappaB mediates tumor cell survival.
  • In met-5A and H2052 cells in which VEGF-R2 was switched off, neither Sema6D-enriched medium nor VEGF had any survival-promoting effect.
  • NF-kappaB activity rose in met-5A cells overexpressing plexin-A1. In H2052 cells, switching off Sema6D or plexin-A1 significantly reduced NF-kappaB activity.
  • Crocidolite strongly increased plexin-A1 and Sema6D protein in three primary mesothelial cultures and met-5A cells after 48 hours. In two cell lines (HMC1 and met-5A) the maximum was reached at 36 hours.
  • Met-5A cells given Sema6D-enriched medium were significantly (P less than 0.05) less sensitive to crocidolite-induced cell death than unstimulated cells. Met-5A cells overexpressing plexin-A1 were more resistant regardless of Sema6D. The NF-kappaB inhibitor BAY 11-7082 almost completely abolished this protection.
• The authors' conclusion: The authors concluded that a plexin-A1-dependent pathway is critical in human malignant pleural mesothelioma cells. In their view, it regulates cell survival and anchorage-independent growth by controlling VEGF-R2-dependent NF-kappaB activity. They also wrote that this signaling may be responsible for the survival of nonmalignant mesothelial cells after crocidolite exposure.
• Limitations the authors state:
  • The exact mechanism of the tumor-promoting activity of Sema6D and plexin-A1 remains to be elucidated.
  • Whether plexin-A1 acts through reverse signaling by Sema6D or involves other receptors was not explored.
  • The authors could not exclude that signaling cascades other than NF-kappaB are involved.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Pleural Mesothelioma, Mesothelial Cells, Asbestos Exposure, Tumorigenesis.

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