Modulation of tumor plasticity by senescent cells: Deciphering basic mechanisms and survival pathways to unravel therapeutic options.

Senescence is a cellular state in which the cell loses its proliferative capacity, often irreversibly. Physiologically, it occurs due to a limited capacity of cell division associated with telomere shortening, the so-called replicative senescence. It can also be induced early due to DNA damage, oncogenic activation, oxidative stress, or damage to other cellular components (collectively named induced senescence). Tumor cells acquire the ability to bypass replicative senescence, thus ensuring the replicative immortality, a hallmark of cancer. Many anti-cancer therapies, however, can lead tumor cells to induced senescence. Initially, this response leads to a slowdown in tumor growth. However, the longstanding accumulation of senescent cells (SnCs) in tumors can promote neoplastic progression due to the enrichment of numerous molecules and extracellular vesicles that constitutes the senescence-associated secretory phenotype (SASP). Among other effects, SASP can potentiate or unlock the tumor plasticity and phenotypic transitions, another hallmark of cancer. This review discusses how SnCs can fuel mechanisms that underlie cancer plasticity, like cell differentiation, stemness, reprogramming, and epithelial-mesenchymal transition. We also discuss the main molecular mechanisms that make SnCs resistant to cell death, and potential strategies to target SnCs. At the end, we raise open questions and clinically relevant perspectives in the field.

Subcellular structure, heterogeneity, and plasticity of senescent cells.

Cellular senescence is a state of permanent growth arrest. It can be triggered by telomere shortening (replicative senescence) or prematurely induced by stresses such as DNA damage, oncogene overactivation, loss of tumor suppressor genes, oxidative stress, tissue factors, and others. Advances in techniques and experimental designs have provided new evidence about the biology of senescent cells (SnCs) and their importance in human health and disease. This review aims to describe the main aspects of SnCs phenotype focusing on alterations in subcellular compartments like plasma membrane, cytoskeleton, organelles, and nuclei. We also discuss the heterogeneity, dynamics, and plasticity of SnCs' phenotype, including the SASP, and pro-survival mechanisms. We advance on the multiple layers of phenotypic heterogeneity of SnCs, such as the heterogeneity between inducers, tissues and within a population of SnCs, discussing the relevance of these aspects to human health and disease. We also raise the main challenges as well alternatives to overcome them. Ultimately, we present open questions and perspectives in understanding the phenotype of SnCs from the perspective of basic and applied questions.

Chemical Composition and Cytotoxic Evaluation of the Essential Oil of Phyllogonium viride (Phyllogoniaceae, Bryophyta).

The present study aimed to determine the chemical composition and biological activity of the essential oil obtained from Phyllogonium viride Brid. (Phyllogoniaceae, Bryophyta), whose samples were collected in southern Brazil. For the first time, the cytotoxic activity of the essential oil of P. viride in breast and colorectal tumor cells (MCF-7 and HCT-116) was evaluated, as well as the cytotoxic potential of this oil in non-tumoral cells of human immortalized keratinocytes (HaCaT) via MTT assay. The compounds majorly found in P. viride essential oil were ß-bazzanene (20.30 %), ß-caryophyllene (17.06 %), ß-chamigrene (14.02), and germacrene B (11.72 %). Treatment with P. viride essential oil in the different tested cell lines did not induce any toxicity in most of the tested concentrations. These data contribute to generating new scientific information about this understudied plant species. Furthermore, the chemical characterization of the compounds present in the essential oil of P. viride can lead to greater elucidation of its biotechnological potential.