Intravenous injection of B F melanoma cells
Intravenous injection of B16F10 melanoma cells in Nf-E2-/-mice produces markedly less lung metastatic lesions compared to that in wildtype mice . This provides one of the strongest confirmations for the role of platelets in hematological dissemination of tumor cells although bone tissues were not examined. The platelet-type von Willebrand disease (Pt-vWD) is characterized by a higher affinity of platelets to the soluble form of von Willebrand factor due to a point mutation in GPIbα to a persistent thrombocytopenia and a bleeding disorder. Transgenic mice reproducing the Pt-vWD exhibit increasing number of MKs and a high bone mass phenotype . Due to its specific expression in MKs and platelets, GPIbα has been suggested as target for the development of new therapies against skeletal metastasis. Nevertheless, the role of GPIbα in tumor cell-induced platelet aggregation remains controversial, with some reports showing its positive contribution , and others described no impact of blocking GPIbα human leukocyte elastase . Also, in experimental metastasis models using B16F10 melanoma cells, mice lacking GPIbα developed a lower number of lung metastases than wild type mice . In a striking contrast, functional inhibition of GPIbα using monoclonal antibodies in vivo led to a strong increase in pulmonary metastasis . The reason for these discrepancies remain to be established.
Conclusion Due to their specific location in vascular sinusoids, MKs appear as tempting targets for blocking skeletal metastases because they might be the first cells encountered by metastatic cancer cells at early steps of bone colonization. Although TPO blocks PC3-induced skeletal metastasis in mice, such a regimen is unlikely to be transferred to the clinic because of an immediate increase in the circulating platelet count that could favor interactions between tumor cells and platelets, thereby increasing the risk of venous thromboembolism . Targeting platelets and/or MKs may help inhibiting cancer metastases to the bone. However, to achieve efficacy and safety, strategies to block platelets’ prometastatic activity will need to maintain platelets’ vital functions in hemostasis while increasing the number of MKs in the bone marrow preventing bone degradation and stimulating bone formation.
Acknowledgements This review was supported by grants from the INSERM, the University of Lyon (OP), the Comité Départemental de la Loire de la Ligue Contre le Cancer (OP) and the French Fondation pour la Recherche sur le Cancer (Grant no. PJA20151203151), ARC (OP). RL has a grant fellowship from the Université Aix-Marseille (AMU).
Introduction The skeleton is the most prevalent site of metastasis for several cancer types. Skeletal metastasis is associated with a reduced quality of life owing to prolonged pain, poor therapeutic success and low survival rate [1,2]. The initial stages that underpin this poor outcome is laid by the extravasation and lodging of circulating tumour cells in the bone marrow microenvironment, a process that in most patients precedes the primary tumour detection. Disseminated tumour cells (DTCs) may survive within the bone marrow microenvironment in the state of dormancy (cell cycle arrest) for very long periods. While a subset of patients develop detectable metastases as late as two-to-three decades post primary tumour detection, others show no signs of relapse despite the detection of DTCs in bone postmortem [2–4]. Such clinical evidence argue in favor of targeting DTCs within the bone microenvironment, rather than targeting the initial steps of tumour cell extravasation and dissemination. Designing strategies to target DTCs within the bone marrow microenvironment is likely to facilitate the development of therapeutic regimes that delay or prevent metastatic relapse. However, this requires fundamental understanding of the mechanisms that lead to dormancy and subsequent reactivation of cancer cells. Existing therapeutic strategies target and slow down progression in the late stage of the disease; but these therapies are not curative [1–4]. Despite its tremendous impact on the therapeutic outcome, our understanding of the early stage (survival, quiescence, migration and proliferation of cancer cells in bone) of the disease remains poor. Multiple lines of evidence demonstrate that tumour cells are regulated in a non-cell-autonomous manner. Notably, recent findings highlight the important roles of the microenvironment in determining the fate of DTCs [5,6].