SASP-Dependent Interactions between Senescent Cells and Platelets Modulate Migration and Invasion of Cancer Cells.

Alterations in platelet aggregation are common in aging individuals and in the context of age-related pathologies such as cancer. So far, however, the effects of senescent cells on platelets have not been explored. In addition to serving as a barrier to tumor progression, cellular senescence can contribute to remodeling tissue microenvironments through the capacity of senescent cells to synthesize and secrete a plethora of bioactive factors, a feature referred to as the senescence-associated secretory phenotype (SASP). As senescent cells accumulate in aging tissues, sites of tissue injury, or in response to drugs, SASP factors may contribute to increase platelet activity and, through this mechanism, generate a microenvironment that facilitates cancer progression. Using in vitro models of drug-induced senescence, in which cellular senescence was induced following exposure of mammary epithelial cells (MCF-10A and MCF-7) and gastric cancer cells (AGS) to the CDK4/6 inhibitor Palbociclib, we show that senescent mammary and gastric cells display unique expression profiles of selected SASP factors, most of them being downregulated at the RNA level in senescent AGS cells. In addition, we observed cell-type specific differences in the levels of secreted factors, including IL-1ß, in media conditioned by senescent cells. Interestingly, only media conditioned by senescent MCF-10A and MCF-7 cells were able to enhance platelet aggregation, although all three types of senescent cells were able to attract platelets in vitro. Nevertheless, the effects of factors secreted by senescent cells and platelets on the migration and invasion of non-senescent cells are complex. Overall, platelets have prominent effects on migration, while factors secreted by senescent cells tend to promote invasion. These differential responses likely reflect differences in the specific arrays of secreted senescence-associated factors, specific factors released by platelets upon activation, and the susceptibility of target cells to respond to these agents.

The Potential Role of Senescence As a Modulator of Platelets and Tumorigenesis.

In addition to thrombus formation, alterations in platelet function are frequently observed in cancer patients. Importantly, both thrombus and tumor formation are influenced by age, although the mechanisms through which physiological aging modulates these processes remain poorly understood. In this context, the potential effects of senescent cells on platelet function represent pathophysiological mechanisms that deserve further exploration. Cellular senescence has traditionally been viewed as a barrier to tumorigenesis. However, far from being passive bystanders, senescent cells are metabolically active and able to secrete a variety of soluble and insoluble factors. This feature, known as the senescence-associated secretory phenotype (SASP), may provide senescent cells with the capacity to modify the tissue environment and, paradoxically, promote proliferation and neoplastic transformation of neighboring cells. In fact, the SASP-dependent ability of senescent cells to enhance tumorigenesis has been confirmed in cellular systems involving epithelial cells and fibroblasts, leaving open the question as to whether similar interactions can be extended to other cellular contexts. In this review, we discuss the diverse functions of platelets in tumorigenesis and suggest the possibility that senescent cells might also influence tumorigenesis through their ability to modulate the functional status of platelets through the SASP.

Palbociclib-induced autophagy and senescence in gastric cancer cells.

Targeting cyclin D-CDK4/6 kinase complexes has recently been shown to increase the survival of breast cancer patients with estrogen receptor positive breast tumors. Based on these outcomes, CDK4/6 inhibitors are currently being tested, alone o in combination with other drugs, in the treatment of other malignancies characterized by hyper-activation of cyclin D-CDK4/6 complexes. Nonetheless, a better understanding of the cellular processes that are implemented in response to CDK4/6 inhibition is necessary to expand the therapeutic window and confront the development of drug resistance. Herein, we show that, similar to mammary cells, gastric cancer cells are sensitive to the CDK4/6 inhibitor Palbociclib. Inhibition of CDK4/6 in gastric cancer cells leads to the implementation of cellular senescence. However, whether or not this response is accompanied by induction of autophagy seems to depend on both the pRB and p53 status. In cells retaining expression of both tumor suppressive proteins (AGS gastric cancer cells), exposure to Palbociclib induces senescence and autophagy. However, the simultaneous blockade of CDK4/6 and autophagy in these cells exacerbates the senescence phenotype, an indication that autophagy in these experimental settings represents an adaptive mechanism that promotes cell survival rather than being an effector mechanism of senescence. Interestingly, knocking down p53 resulted in senescence reduction and autophagy blockade, the latter apparently involving a disruption of the degradation of autophagosome cargo.

[A critical view of the human resources planning and autonomous managed hospitals in Chile]. / Reflexión sobre la planificación de los recursos humanos y la autonomía de gestión en los hospitales de Chile.

In 2002, Chile began a process of health reform where autonomously managed establishments as part of a network were introduced into the public health provider system. However, gaps in human resource planning for the needs of these establishments are evident. One fundamental aspect that was absent in the planning of human resources in health during the health reform process was a needs assessment for professionals in the public health sector. Moreover, the networked autonomous establishments now demand a debate on the issues of flexible contracting of human resources. For the current scenario of health reform implementation, the lack of a policy for the requirements of human resources in diverse aspects of the process constitutes a drawback that still can be corrected.

Reflexión sobre la planificacion de los recursos humanos y la autonomía de gestión en los hospitales de Chile / A Critical View of the Human Resources Planning and Autonoumus Managed Hospitals in Chile

En el año 2002 Chile inició un proceso de reforma al sistema de salud en la cual se introduce la figura de los establecimientos autogestionados en red. Sin embargo, destacan brechas en aspectos como la planificación de los recursos humanos y el requerimiento de los establecimientos autogestionados en red.Un aspecto fundamental que estuvo ausente en la planificación de los recursos humanos en salud en el proceso de reforma fue no determinar la necesidad de profesionales necesarios para el escenario de reforma del sector. Además, los nuevos establecimientos autogestionados en red demandan debatir respecto a temas como la flexibilización en las formas de contratación de los recursos humanos en salud.Para el actual escenario de implementación de la reforma de salud, la ausencia de una política para los requerimientos de recursos humanos en los diversos aspectos del proceso constituye una desventaja que aún puede ser corregida (AU)

In 2002, Chile began a process of health reform where autonomously managed establishments as part of a network were introduced into the public health provider system. However, gaps in human resource planning for the needs of these establishments are evident.One fundamental aspect that was absent in the planning of human resources in health during the health reform process was a needs assessment for professionals in the public health sector. Moreover, the networked autonomous establishments now demand a debate on the issues of flexible contracting of human resources.For the current scenario of health reform implementation, the lack of a policy for the requirements of human resources in diverse aspects of the process constitutes a drawback that still can be corrected (AU)