Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A2.

Because metastasis is associated with the majority of cancer-related deaths, its prevention is a clinical aspiration. Prostanoids are a large family of bioactive lipids derived from the activity of cyclooxygenase-1 (COX-1) and COX-2. Aspirin impairs the biosynthesis of all prostanoids through the irreversible inhibition of both COX isoforms. Long-term administration of aspirin leads to reduced distant metastases in murine models and clinical trials, but the COX isoform, downstream prostanoid, and cell compartment responsible for this effect are yet to be determined. Here, we have shown that aspirin dramatically reduced lung metastasis through inhibition of COX-1 while the cancer cells remained intravascular and that inhibition of platelet COX-1 alone was sufficient to impair metastasis. Thromboxane A2 (TXA2) was the prostanoid product of COX-1 responsible for this antimetastatic effect. Inhibition of the COX-1/TXA2 pathway in platelets decreased aggregation of platelets on tumor cells, endothelial activation, tumor cell adhesion to the endothelium, and recruitment of metastasis-promoting monocytes/macrophages, and diminished the formation of a premetastatic niche. Thus, platelet-derived TXA2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and identifies COX-1/TXA2 signaling as a target for the prevention of metastasis.

Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice.

Tissue factor (TF) expression by tumor cells correlates with metastasis clinically and supports metastasis in experimental settings. However, the precise pathways coupling TF to malignancy remain incompletely defined. Here, we show that clot formation by TF indirectly enhances tumor cell survival after arrest in the lung, during experimental lung metastasis, by recruiting macrophages characterized by CD11b, CD68, F4/80, and CX(3)CR1 (but not CD11c) expression. Genetic or pharmacologic inhibition of coagulation, by either induction of TF pathway inhibitor ex-pression or by treatment with hirudin, respectively, abrogated macrophage recruitment and tumor cell survival. Furthermore, impairment of macrophage function, in either Mac1-deficient mice or in CD11b-diphtheria toxin receptor mice in which CD11b-positive cells were ablated, decreased tumor cell survival without altering clot formation, demonstrating that the recruitment of functional macrophages was essential for tumor cell survival. This effect was independent of NK cells. Moreover, a similar population of macrophages was also recruited to the lung during the formation of a premetastatic niche. Anticoagulation inhibited their accumulation and prevented the enhanced metastasis associated with the formation of the niche. Our study, for the first time, links TF induced coagulation to macrophage recruitment in the metastatic process.

Estructura, correlatos y predictores del estrés por aculturación: El caso de personas refugiadas colombianas en Costa Rica / Structure, correlates and predictors of acculturation stress: A case study with colombian refugees in Costa Rica

Cien personas refugiadas colombianas completaron un cuestionario que medía el estrés experimentado durante el proceso de adaptación a la sociedad costarricense, las redes de apoyo construidas en Costa Rica, la frecuencia con que se han visto discriminadas y su nivel de salud mental. Los datos muestran que el estrés por aculturación se estructuran en cuatro dimensiones: el estrés experimentado por los preparativos para la salida, el estrés derivado de su condición de refugiados, el estrés experimentado ante las necesidades económicas y el estrés vivido ante los retos de la adaptación cultural a la sociedad costarricense. Los preparativos para la salida del país son los eventos de mayor estrés reportado. La discriminación percibida y los años de residencia en Costa Rica aparecieron como los principales predictores de los tipos de estrés posinmigración, una vez controlados los efectos de la salud y las redes de apoyo.

One hundred colombian refugees completed a questionnaire measuring the level of stress they have experienced during the process of adaptation to the Costa Rican society; the social networks they have built in Costa Rica; the frequency with which they have been discriminated against; and their mental health. Data show four dimensions for acculturative stress: the stress produced by the arrangements to leave Colombia; the stress derived from their status as refugees; the stress derived from their socioeconomic needs; and the stress resulting from coping with the demands of the social and cultural adaptation to the host society. Participants reported significant higher levels of stress when planning the emigration from Colombia. Perceived discrimination and years of residence in Costa Rica were the principal predictors of acculturative stress in Costa Rica, above and below of the effect of other potential predictors, as social networks and mental health.