Cancer–malaria: hidden connections

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Abstract

Cancer and malaria exemplify two maladies historically assigned to separated research spaces. Cancer, on the one hand, ranks among the top priorities in the research agenda of developed countries. Its rise is mostly explained by the ageing of these populations and linked to environment and lifestyle. Malaria, on the other hand, represents a major health burden for developing countries in the Southern Hemisphere. These two diseases also belong to separate fields of medicine: non-communicable diseases for cancer and communicable diseases for malaria.

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Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein.

Ali Salanti, Thomas M Clausen, Mette Ø. Agerbæk … (2015)

Plasmodium falciparum engineer infected erythrocytes to present the malarial protein, VAR2CSA, which binds a distinct type chondroitin sulfate (CS) exclusively expressed in the placenta. Here, we show that the same CS modification is present on a high proportion of malignant cells and that it can be specifically targeted by recombinant VAR2CSA (rVAR2). In tumors, placental-like CS chains are linked to a limited repertoire of cancer-associated proteoglycans including CD44 and CSPG4. The rVAR2 protein localizes to tumors in vivo and rVAR2 fused to diphtheria toxin or conjugated to hemiasterlin compounds strongly inhibits in vivo tumor cell growth and metastasis. Our data demonstrate how an evolutionarily refined parasite-derived protein can be exploited to target a common, but complex, malignancy-associated glycosaminoglycan modification.

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Chondroitin sulfates play a major role in breast cancer metastasis: a role for CSPG4 and CHST11 gene expression in forming surface P-selectin ligands in aggressive breast cancer cells

CRAIG A. COONEY, FARIBA JOUSHEGHANY, AIWEI YAO-BORENGASSER … (2011)

Introduction We have previously demonstrated that chondroitin sulfate glycosaminoglycans (CS-GAGs) on breast cancer cells function as P-selectin ligands. This study was performed to identify the carrier proteoglycan (PG) and the sulfotransferase gene involved in synthesis of the surface P-selectin-reactive CS-GAGs in human breast cancer cells with high metastatic capacity, as well as to determine a direct role for CS-GAGs in metastatic spread. Methods Quantitative real-time PCR (qRT-PCR) and flow cytometry assays were used to detect the expression of genes involved in the sulfation and presentation of chondroitin in several human breast cancer cell lines. Transient transfection of the human breast cancer cell line MDA-MB-231 with the siRNAs for carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) and chondroitin sulfate proteoglycan 4 (CSPG4 ) was used to investigate the involvement of these genes in expression of surface P-selectin ligands. The expression of CSPG4 and CHST11 in 15 primary invasive breast cancer clinical specimens was assessed by qRT-PCR. The role of CS-GAGs in metastasis was tested using the 4T1 murine mammary cell line (10 mice per group). Results The CHST11 gene was highly expressed in aggressive breast cancer cells but significantly less so in less aggressive breast cancer cell lines. A positive correlation was observed between the expression levels of CHST11 and P-selectin binding to cells (P < 0.0001). Blocking the expression of CHST11 with siRNA inhibited CS-A expression and P-selectin binding to MDA-MB-231 cells. The carrier proteoglycan CSPG4 was highly expressed on the aggressive breast cancer cell lines and contributed to the P-selectin binding and CS-A expression. In addition, CSPG4 and CHST11 were over-expressed in tumor-containing clinical tissue specimens compared with normal tissues. Enzymatic removal of tumor-cell surface CS-GAGs significantly inhibited lung colonization of the 4T1 murine mammary cell line (P = 0.0002). Conclusions Cell surface P-selectin binding depends on CHST11 gene expression. CSPG4 serves as a P-selectin ligand through its CS chain and participates in P-selectin binding to the highly metastatic breast cancer cells. Removal of CS-GAGs greatly reduces metastatic lung colonization by 4T1 cells. The data strongly indicate that CS-GAGs and their biosynthetic pathways are promising targets for the development of anti-metastatic therapies.

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CD82/KAI1 Maintains the Dormancy of Long-Term Hematopoietic Stem Cells through Interaction with DARC-Expressing Macrophages.

Jin-Gang Hur, Jae-Il Choi, Hwan Hee Lee … (2016)

Hematopoiesis is regulated by crosstalk between long-term repopulating hematopoietic stem cells (LT-HSCs) and supporting niche cells in the bone marrow (BM). Here, we examine the role of CD82/KAI1 in niche-mediated LT-HSC maintenance. We found that CD82/KAI1 is expressed predominantly on LT-HSCs and rarely on other hematopoietic stem-progenitor cells (HSPCs). In Cd82(-/-) mice, LT-HSCs were selectively lost as they exited from quiescence and differentiated. Mechanistically, CD82-based TGF-β1/Smad3 signaling leads to induction of CDK inhibitors and cell-cycle inhibition. The CD82 binding partner DARC/CD234 is expressed on macrophages and stabilizes CD82 on LT-HSCs, promoting their quiescence. When DARC(+) BM macrophages were ablated, the level of surface CD82 on LT-HSCs decreased, leading to cell-cycle entry, proliferation, and differentiation. A similar interaction appears to be relevant for human HSPCs. Thus, CD82 is a functional surface marker of LT-HSCs that maintains quiescence through interaction with DARC-expressing macrophages in the BM stem cell niche.

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Journal

Journal ID (nlm-ta): Open Biol

Journal ID (iso-abbrev): Open Biol

Journal ID (publisher-id): RSOB

Journal ID (hwp): royopenbio

Title: Open Biology

Publisher: The Royal Society

ISSN (Electronic): 2046-2441

Publication date Collection: October 2018

Publication date (Electronic): 31 October 2018

Publication date PMC-release: 31 October 2018

Volume: 8

Issue: 10

Electronic Location Identifier: 180127

Affiliations

[1 ]Institut Curie, PSL Research University, Département de Recherche Translationnelle , 75005 Paris, France

[2 ]Institut Curie, PSL Research University, Hôpital René Huguenin, Laboratoire d'Oncobiologie, Pôle Pathologie-Génétique-Immunologie-Hémobiologie , 92210 Saint-Cloud, France

[3 ]IBM Research Africa , Johannesburg, South Africa

[4 ]Center for Research Computing, Eck Institute for Global Health, University of Notre Dame , Notre Dame, IN 46656, USA

Author notes

e-mail: gsiwo@ 123456nd.edu

Author information

Akpéli V. Nordor http://orcid.org/0000-0003-3541-0221

Geoffrey H. Siwo http://orcid.org/0000-0003-0726-997X

Article

Publisher ID: rsob180127

DOI: 10.1098/rsob.180127

PMC ID: 6223206

PubMed ID: 30381365

SO-VID: f766d47c-61dc-4576-926a-3ca92a1a5365

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Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

History

Date received : 24 July 2018

Date accepted : 2 October 2018

Funding

Funded by: Association pour la recherche en cancerologie de Saint-Cloud (ARCS);

Funded by: ADEBIOPHARM;

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cover-date October 2018

ScienceOpen disciplines: Life sciences

Keywords: cancer,malaria,placenta,genetics,immunology,immunotherapy

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ScienceOpen disciplines: Life sciences

Keywords: cancer, malaria, placenta, genetics, immunology, immunotherapy

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Cancer–malaria: hidden connections

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Cancer Immunotherapy

Most cited references 17

Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein.

Chondroitin sulfates play a major role in breast cancer metastasis: a role for CSPG4 and CHST11 gene expression in forming surface P-selectin ligands in aggressive breast cancer cells

CD82/KAI1 Maintains the Dormancy of Long-Term Hematopoietic Stem Cells through Interaction with DARC-Expressing Macrophages.

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