The impact of Aggrus/podoplanin on platelet aggregation and tumour metastasis

Our plain-English summary of The impact of Aggrus/podoplanin on platelet aggregation and tumour metastasis, by N. Fujita, S. Takagi (Journal of Biochemistry, 2012).

The study

• Authors: N. Fujita, S. Takagi
• Journal: Journal of Biochemistry
• Published: 2012;152(5):407-13
• Type of article: Review
• Cited by: 50 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Platelets are small blood components that play indispensable roles in the initial stages of coagulation. In addition to their role in haemostasis, platelets participate in inflammation and tissue regeneration under physiological conditions. Recent studies also revealed the role of platelets under pathological conditions, including the oncogenic process. Platelets enhance tumour growth and metastasis by secreting many growth factors and angiogenic factors or by forming a coat around tumour cells in the blood stream. We previously discovered Aggrus (also known as podoplanin, gp36, gp38P, T1alpha and OTS-8) expressed on tumour cell surfaces as a key molecule for tumour-induced platelet aggregation. Aggrus expression is increased in various malignant tumours such as squamous cell carcinomas, mesotheliomas, glioblastomas and osteosarcomas. Detailed analysis revealed that Aggrus contains three tandem repeats of platelet aggregation-stimulating (PLAG) domains that are associated with its platelet aggregation-inducing ability. PLAG domains of Aggrus are involved in binding to its platelet receptor, C-type lectin-like receptor 2 (CLEC-2). Neutralizing monoclonal antibodies that interfere with Aggrus-CLEC-2 binding attenuate Aggrus-induced platelet aggregation, tumour cell growth and metastasis formation. Aggrus is also expressed in advanced atherosclerotic lesions, suggesting that Aggrus is associated with thrombus formation on disrupted atherosclerotic lesions. These data suggest that Aggrus is a promising cell surface target for developing new therapies against cancer and thrombosis.

In plain English

This article was a review, not a new study. The authors described research, much from their own laboratory, on Aggrus (also called podoplanin), a tumour-cell surface protein that makes blood platelets clump. Experiments on how Aggrus drives cancer spread, and on blocking it, used cell lines and mice. The review also cites human tumour findings, including that Aggrus in cancer-associated fibroblasts predicts poor prognosis of lung adenocarcinomas, but no human trial of Aggrus-blocking treatment. It covered mouse colon cancer clones whose platelet-clumping ability matched their ability to spread, the 2003 cloning of Aggrus, three repeated regions (PLAG domains) needed for clumping and spread, and the 2007 finding by others that CLEC-2 is Aggrus's partner on platelets. Antibodies that block Aggrus, including P2-0, reduced lung spread of cells in mice. The article says Aggrus expression is increased in tumours including mesotheliomas, but gives no data on mesothelioma, asbestos or fibre exposure. The authors concluded that small-molecule drugs blocking Aggrus binding to CLEC-2 should be developed in future. They noted that antibodies may be too costly for some uses.

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: Narrative review, focused largely on the authors' own earlier laboratory and animal research
• Who was studied: No new study population. The experiments reviewed used tumour cell lines, including mouse colon adenocarcinoma 26 clones (highly metastatic NL-17 and poorly metastatic NL-14), B16 melanoma variants and Chinese hamster ovary cells, and mice. The review also cites reported findings in human tumours.
• Exposure: No asbestos or fibre exposure was studied. The subject is the tumour-cell protein Aggrus/podoplanin and antibodies against it.
• Main results:
  • In the mouse colon cancer clones, the ability to induce platelet aggregation was linked to the ability to metastasize.
  • The authors obtained the Aggrus gene sequence (cDNA) in 2003. Aggrus was found to be identical to podoplanin.
  • Aggrus contains three tandem repeats of a segment the authors named PLAG domains. Mutating conserved threonine residues in these domains removed both platelet-aggregating and metastasis-promoting abilities.
  • CLEC-2 was identified in 2007, in a study the review cites, as the platelet receptor for Aggrus.
  • Platelets lacking CLEC-2 responded normally to classical platelet agonists. The authors interpreted this as indicating that blocking the Aggrus and CLEC-2 interaction may not affect normal blood clotting.
  • The anti-human Aggrus antibody P2-0 suppressed lung metastasis in mice of hamster cells carrying normal Aggrus, but not of cells carrying the G45A or D49A mutant forms.
  • A chimeric humanized version of the antibody, hP2-0, showed strong cell-killing (ADCC and CDC) activities in laboratory tests.
  • The review cites a report that Aggrus expression in cancer-associated fibroblasts predicts poor prognosis of lung adenocarcinomas.
  • The article states that Aggrus expression is increased in various malignant tumours, including mesotheliomas. It presents no mesothelioma-specific data.
• The authors' conclusion: The authors concluded that, in future, small-molecule inhibitors that interfere with Aggrus and CLEC-2 binding should be developed as new anti-platelet drugs. They described Aggrus as a promising target for new therapies against cancer and thrombosis.
• Limitations the authors state:
  • The authors stated that neutralizing anti-Aggrus antibodies may not be appropriate for treating or preventing diseases such as thrombosis because of their high cost.
  • The authors' original antibody, 8F11, recognized mouse Aggrus but not human Aggrus.

Topics

Medical terms in this study, explained in our Lexicon: Podoplanin (D2-40), Metastasis, Inflammation, Squamous Cell Carcinoma, Mesothelioma, Monoclonal Antibody.

Related studies

• Establishment of Mouse Monoclonal Antibody LpMab-13 Against Human Podoplanin — S. Ogasawara, M.K. Kaneko, et al. (2016)
• Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation — S. Takeuchi, K. Fukuda, et al. (2017)
• Podoplanin: An emerging cancer biomarker and therapeutic target — H. Krishnan, J. Rayes, et al. (2018)
• Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model — S. Abe, M.K. Kaneko, et al. (2016)
• Antitumor activity of chLpMab-2, a human-mouse chimeric cancer-specific antihuman podoplanin antibody, via antibody-dependent cellular cytotoxicity — M.K. Kaneko, S. Yamada, et al. (2017)
• Value of podoplanin as an immunohistochemical marker in tumor diagnosis: a review and update — N.G. Ordóñez (2014)

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