The Interaction of Platelets with Colorectal Cancer Cells Inhibits Tumor Growth but Promotes Metastasis.

Platelets promote metastasis, however, their role in tumor growth remains controversial. Here, we investigated the effect of platelet interactions with colorectal tumor cells. Platelets extravasated into the tumor microenvironment and interacted with tumor cells in a cadherin-6-dependent manner. The interaction induced platelet spreading, release of their granule content, and the generation of three types of microparticles (iMP) that expressed platelet markers, tumor markers, or both. The presence of iMPs was confirmed in colorectal cancer tissue specimens. Platelets significantly reduced tumor growth and increased intratumoral macrophages. This was mediated by iMP recruitment of macrophages via the chemoattractants RANTES, MIF, CCL2, and CXCL12 and activation of their tumor cell killing capacity through IFNγ and IL4, which led to cell-cycle arrest of tumor cells in a p21-dependent manner. In contrast, in the bloodstream, iMPs activated endothelial cells and platelets and induced epithelial-to-mesenchymal transition of tumor cells, promoting metastasis. Altogether, these results indicate that depending on the environment, local or bloodstream, the consequences of the interactions between platelets and a tumor may promote or prevent cancer progression. SIGNIFICANCE: Tumor cell interaction with platelets produces chimeric extracellular vesicles that suppress primary tumor growth by activating tumor-eliminating macrophages, while promoting metastasis through EMT and endothelial activation.

Neutrophil extracellular traps are associated with the pathogenesis of diffuse alveolar hemorrhage in murine lupus.

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of systemic lupus erythematosus (SLE) and systemic vasculitis. Although initially described to have antibacterial properties, increasing evidence suggests that neutrophil extracellular traps (NETs) have a detrimental role in both autoimmune diseases and acute lung injury. We investigated whether NETs could be detected in a murine model of pristane-induced lupus DAH and contribute to lung injury. Such NETs might constitute a therapeutic target. NETs were characterized by immunofluorescence staining of DNA, neutrophil elastase and citrullinated histones. Evaluation of lung injury was performed by haematoxylin-eosin staining and a quantification program. Clinical status of the mice was assessed by measurement of arterial oxygen saturation and survival curves after recombinant human deoxyribonuclease-1 (Rh-DNase-1) inhalations or polymorphonuclear neutrophil (PMN) depletion. Pristane was found to promote NETs formation in vitro and in vivo. Treatment of mice with Rh-DNase-1 inhalations cleared NETs and reduced lung injury. Clinical status improved significantly, with increased arterial oxygenation and survival. Following PMN depletion, NETs were absent with a subsequent reduction of lung injury and improved arterial oxygenation. These results support a pathogenic role of PMNs and NETs in lung injury during pristane-induced DAH. Targeting NETs with Rh-DNase-1 inhalations could constitute an interesting adjuvant therapy in human DAH.

Impacts of Cancer on Platelet Production, Activation and Education and Mechanisms of Cancer-Associated Thrombosis.

Platelets are small anucleate cells that are traditionally described as the major effectors of hemostasis and thrombosis. However, increasing evidence indicates that platelets play several roles in the progression of malignancies and in cancer-associated thrombosis. A notable cross-communication exists between platelets and cancer cells. On one hand, cancer can "educate" platelets, influencing their RNA profiles, the numbers of circulating platelets and their activation states. On the other hand, tumor-educated platelets contain a plethora of active biomolecules, including platelet-specific and circulating ingested biomolecules, that are released upon platelet activation and participate in the progression of malignancy. The numerous mechanisms by which the primary tumor induces the production, activation and aggregation of platelets (also known as tumor cell induced platelet aggregation, or TCIPA) are directly related to the pro-thrombotic state of cancer patients. Moreover, the activation of platelets is critical for tumor growth and successful metastatic outbreak. The development or use of existing drugs targeting the activation of platelets, adhesive proteins responsible for cancer cell-platelet interactions and platelet agonists should be used to reduce cancer-associated thrombosis and tumor progression.

Effects of platelets on cancer progression.

Platelets are small (2-4 µm), anucleate, hematopoietic cells released by bone marrow megakaryocytes in the bloodstream. For a long time, platelets were described as the major effectors of hemostasis and thrombosis. In 1865, Armand Trousseau demonstrated a close relation between thrombosis and cancer. Subsequently, much clinical and experimental evidence supports the idea that platelets play several roles in the progression of malignancies and in cancer-associated thrombosis. In this review, we will discuss the roles of tumor-educated platelets (TEPs) in the progression of cancer from primary tumors to secondary metastatic outbreaks.

Myostatin gene inactivation prevents skeletal muscle wasting in cancer.

Cachexia is a muscle-wasting syndrome that contributes significantly to morbidity and mortality of many patients with advanced cancers. However, little is understood about how the severe loss of skeletal muscle characterizing this condition occurs. In the current study, we tested the hypothesis that the muscle protein myostatin is involved in mediating the pathogenesis of cachexia-induced muscle wasting in tumor-bearing mice. Myostatin gene inactivation prevented the severe loss of skeletal muscle mass induced in mice engrafted with Lewis lung carcinoma (LLC) cells or in Apc(Min) (/+) mice, an established model of colorectal cancer and cachexia. Mechanistically, myostatin loss attenuated the activation of muscle fiber proteolytic pathways by inhibiting the expression of atrophy-related genes, MuRF1 and MAFbx/Atrogin-1, along with autophagy-related genes. Notably, myostatin loss also impeded the growth of LLC tumors, the number and the size of intestinal polyps in Apc(Min) (/+) mice, thus strongly increasing survival in both models. Gene expression analysis in the LLC model showed this phenotype to be associated with reduced expression of genes involved in tumor metabolism, activin signaling, and apoptosis. Taken together, our results reveal an essential role for myostatin in the pathogenesis of cancer cachexia and link this condition to tumor growth, with implications for furthering understanding of cancer as a systemic disease.