Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation

Abstract

Cellular senescence suppresses cancer by arresting cells at risk of malignant tumorigenesis. However, senescent cells also secrete molecules that can stimulate premalignant cells to proliferate and form tumors, suggesting the senescence response is antagonistically pleiotropic. We show that premalignant mammary epithelial cells exposed to senescent human fibroblasts in mice irreversibly lose differentiated properties, become invasive and undergo full malignant transformation. Moreover, using cultured mouse or human fibroblasts and non-malignant breast epithelial cells, we show that senescent fibroblasts disrupt epithelial alveolar morphogenesis, functional differentiation and branching morphogenesis. Furthermore, we identify MMP-3 as the major factor responsible for the effects of senescent fibroblasts on branching morphogenesis. Our findings support the idea that senescent cells contribute to age-related pathology, including cancer, and describe a new property of senescent fibroblasts - the ability to alter epithelial differentiation - that might also explain the loss of tissue function and organization that is a hallmark of aging.

Drug-induced senescence bystander proliferation in prostate cancer cells in vitro and in vivo

“…We acknowledge that a transient increase in proliferation may be induced prior to the development of a palpable tumour, but clearly, the long-term impact on tumour size was not significant. Technically similar mixing experiments in immune-deficient mice have been performed using senescent fibroblasts and a stimulatory effect was easily demonstrated using multiple immortalised and tumorigenic cell lines (Krtolica et al, 2001;Parrinello et al, 2005;Bavik et al, 2006). In vivo, these studies utilised equivalent numbers of proliferating and senescent cells similar to our methods.…”

Profiling influences of senescent and aged fibroblasts on prostate carcinogenesis

“…For example, senescent but not pre-senescent breast fibroblasts were shown to transform immortal, non-neoplastic breast epithelial cell lines in a mouse xenograft model and to promote progression of neoplastic cell lines (Krtolica et al, 2001). Senescent fibroblasts also inhibited the normal differentiation programme of mammary gland development (Parrinello et al, 2005). Bavik et al (2006) extended these observations made in breast cancer to studies of prostate cancer and demonstrated that senescent prostate fibroblasts can stimulate the growth of preneoplastic and neoplastic prostate epithelium in vitro.…”

“…Interestingly, although the cell-cycle consequences of senescence are universal, the mechanisms that underlie the state of growth arrest and the gene expression programmes reflecting these varied mechanisms exhibit substantial differences (Zhang, 2007). Paradoxically, although it is thought that the cellular senescence programme may have developed as a mechanism to prevent malignant transformation by preventing continued replication in the setting of carcinogenic events (Roninson, 2003;Parrinello et al, 2005), accumulating data suggest that over time, residual senescent cells may alter the microenvironment to promote carcinogenesis in remaining non-senescent epithelium. This scenario has been suggested to represent an example of evolutionary antagonistic pleiotropy whereby natural selection would retain a mechanism (senescence) that protected the organism from a detrimental event (carcinogenesis), but this selected mechanism could have adverse consequences after selective pressures were no longer operative (Krtolica et al, 2001).…”

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…Subsequent studies established that senescent cells change their expression profile to a senescence-associated secretory phenotype (SASP) [88]. SASP is characterized by expression of cytokines and chemokines leading to an inflammatory response that promotes leukocyte infiltration that is immunosuppressive [89][90][91]. Among others, senescent fibroblasts secrete the canonical pro-inflammatory factors IL-6, IL-1, IL-8, CXCL1, and CXCL2 [88].…”