Abstract
Cellular senescence has been perceived as a barrier against carcinogenesis. However, the senescence-associated secretory phenotype (SASP) of senescent cells can promote tumorigenesis. Here, we show senescent tumour cells are frequently present in the front region of collective invasion of papillary thyroid carcinoma (PTC), as well as lymphatic channels and metastatic foci of lymph nodes. In in vitro invasion analysis, senescent tumour cells exhibit high invasion ability as compared with non-senescent tumour cells through SASP expression. Collective invasion in PTC is led by senescent tumour cells characterized by generation of a C-X-C-motif ligand (CXCL)12 chemokine gradient in the front region. Furthermore, senescent cells increase the survival of cancer cells via CXCL12/CXCR4 signalling. An orthotopic xenograft in vivo model also shows higher lymphatic vessels involvement in the group co-transplanted with senescent cells and cancer cells. These findings suggest that senescent cells are actively involved in the collective invasion and metastasis of PTC.
Highlights
Cellular senescence has been perceived as a barrier against carcinogenesis
We examined senescent cells in various tumour types, including thyroid, breast, colon and stomach cancers by SA-b-Gal staining (Supplementary Fig. 1), a standard biomarker of senescence, and found that senescent cells were frequently identified in thyroid cancer, and mostly in BRAFV600E-expressing papillary thyroid carcinoma (PTC)
To determine whether p16INK4A immunopositive senescent cells were thyroid tumour cells or stromal cells, we assessed the expression of BRAFV600E using VE1, a BRAFV600E-specific monoclonal antibody and thyroid transcription factor-1 (TTF-1) in formalin-fixed paraffin embedded (FFPE) tissues of BRAFV600E-expressing PTC
Summary
Cellular senescence has been perceived as a barrier against carcinogenesis. the senescence-associated secretory phenotype (SASP) of senescent cells can promote tumorigenesis. Most cancers are composed of varying degrees of heterogeneous subpopulations with distinct biologic properties involving proliferative ability, genetic alterations, signal pathways, drug or immune response, angiogenic potential, cell metabolism, motility, secretome and senescence, as well as different abilities for invasion and metastasis; certain cancer cells invade in the front of collective invasion as leaders whereas others are located in the rear and follow[6,7,8] Among these biological properties, cellular senescence has been suggested as a barrier against carcinogenesis, because senescence induced by oncogenic activation (oncogene-induced senescence; OIS) is commonly observed in premalignant tumours, but rare in their malignant counterparts[9]. We analysed BRAFV600E-expressing PTC tissues from patients and employed an in vitro senescent thyrocyte model using BRAFV600E oncogenic activation, which is known as the most common oncogenic driver in PTC17, and applied this in vitro model and an orthotopic xenograft nude mouse model to characterize senescent cells and determine their involvement in collective invasion of PTC
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