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5TGM1 cells co-localized with platelets in femur of syngeneic murine model.

Purpose: Tumor cell–platelet interactions contribute to tumor progression and metastasis in solid tumors. However, the role of platelets in hematological malignancies is not clear. We investigated the association of platelet activation status with clinical stages in multiple myeloma (MM) patients and explored the role of platelets in MM progression.Experimental Design: Platelets were obtained from healthy donors and MM patients. We examined platelet activation status in MM patients by flow cytometry and transmission electron microscopy. We also observed the enriched pathways that are involved with platelet activation in RNA sequencing of platelets. MM cell lines were used to assess the effect of platelets on MM cell proliferation in vitro and their engraftment in vivo. RNA sequencing of MM cell lines was performed to explore molecular mechanisms underlying MM cell–platelet interaction and a CRISPR/Cas9 knockout approach was used for validation.Results: Platelets from MM patients were highly activated with disease progression. RNA sequencing of platelets revealed that genes involved in platelets were enriched in patients with smoldering MM (SMM) or MM. Platelets promoted MM cell proliferation in vitro and contributed to tumor engraftment in bone marrow in vivo. RNA sequencing revealed that IL-1β was upregulated in MM cell lines co-cultured with platelets, whereas IL-1β knockout in MM cell lines abrogated the effects of platelets on MM cell proliferation and engraftment in vivo.Conclusions: Platelets from MM patients were highly activated with disease progression. IL-1β is critical to platelet-mediated MM progression and might be a potential target for MM treatment. Clin Cancer Res; 24(10); 2430–9. ©2018 AACR.

Treatment of CD41 Ab reduced the platelet count in SCID-beige mice.

IL-1b knockout MM cells were generated and confirmed.

Fifteen cytokines were secreted by the MM cell-mediated platelet activation.

Tumor-interacting platelets could be removed by wash process completely.

Clinical information of patients with MGUS, SMM, or MM.

Murine platelets enhance proliferation rate of murine multiple myeloma cells in vitro.

Co-culture with platelets increases the IL-1β mRNA levels in MM cells.

Exosomes are small vesicles ranging in size between 30 and 150 nm, derived from the luminal membranes of the endosome and are constitutively released by fusion with the cell membrane. Several studies have revealed that exosomes play crucial roles in mediating local and systemic cell communication through the horizontal transfer of information in the form of nucleic material and proteins. This is particularly relevant in the context of the tumor-microenvironment cross talk. Here we describe the method of isolating exosomes and their role in modifying the tumor environment and more specifically in enabling metastasis and promoting angiogenesis.

Multiple myeloma (MM) is an incurable disease that progresses from a premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS) and an intermediate stage of smoldering multiple myeloma (SMM). Recent major advances in therapy with more effective and less toxic treatments have brought reconsideration of early therapeutic intervention in management of SMM, with the goal of reducing progression of the disease before the occurrence of end-organ damage to MM and improving survival. Key to this effort is accurate identification of patients at high risk of progression who would truly benefit from early intervention. In this review, we discuss the current definitions, risk factors, risk stratification, prognosis, and management of MGUS and SMM, as well as new emerging therapeutic options under active investigation.