Senescent cells, formed in response to physiological and oncogenic stresses, facilitate protection from tumourigenesis and aid in tissue repair. However, accumulation of such cells in tissues ...contributes to age-related pathologies. Resistance of senescent cells to apoptotic stimuli may contribute to their accumulation, yet the molecular mechanisms allowing their prolonged viability are poorly characterized. Here we show that senescent cells upregulate the anti-apoptotic proteins BCL-W and BCL-XL. Joint inhibition of BCL-W and BCL-XL by siRNAs or the small-molecule ABT-737 specifically induces apoptosis in senescent cells. Notably, treatment of mice with ABT-737 efficiently eliminates senescent cells induced by DNA damage in the lungs as well as senescent cells formed in the epidermis by activation of p53 through transgenic p14(ARF). Elimination of senescent cells from the epidermis leads to an increase in hair-follicle stem cell proliferation. The finding that senescent cells can be eliminated pharmacologically paves the way to new strategies for the treatment of age-related pathologies.
Cellular senescence is a program activated by normal cells in response to various types of stress. These include telomere uncapping, DNA damage, oxidative stress, oncogene activity and others. ...Senescence can occur following a period of cellular proliferation or in a rapid manner in response to acute stress. Once cells have entered senescence, they cease to divide and undergo a series of dramatic morphologic and metabolic changes. Cellular senescence is thought to play an important role in tumor suppression and to contribute to organismal aging, but a detailed description of its physiologic occurrence in vivo is lacking. Recent studies have provided important insights regarding the manner by which different stresses and stimuli activate the signaling pathways leading to senescence. These studies reveal that a population of growing cells may suffer from a combination of different physiologic stresses acting simultaneously. The signaling pathways activated by these stresses are funneled to the p53 and Rb proteins, whose combined levels of activity determine whether cells enter senescence. Here we review recent advances in our understanding of the stimuli that trigger senescence, the molecular pathways activated by these stimuli, and the manner by which these signals determine the entry of a population of cells into senescence.
Much interest is currently focused on the emerging role of tumor-stroma interactions essential for supporting tumor progression. Carcinoma-associated fibroblasts (CAFs), frequently present in the ...stroma of human breast carcinomas, include a large number of myofibroblasts, a hallmark of activated fibroblasts. These fibroblasts have an ability to substantially promote tumorigenesis. However, the precise cellular origins of CAFs and the molecular mechanisms by which these cells evolve into tumor-promoting myofibroblasts remain unclear. Using a coimplantation breast tumor xenograft model, we show that resident human mammary fibroblasts progressively convert into CAF myofibroblasts during the course of tumor progression. These cells increasingly acquire two autocrine signaling loops, mediated by TGF-β and SDF-1 cytokines, which both act in autostimulatory and cross-communicating fashions. These autocrine-signaling loops initiate and maintain the differentiation of fibroblasts into myofibroblasts and the concurrent tumor-promoting phenotype. Collectively, these findings indicate that the establishment of the self-sustaining TGF-β and SDF-1 autocrine signaling gives rise to tumor-promoting CAF myofibroblasts during tumor progression. This autocrine-signaling mechanism may prove to be an attractive therapeutic target to block the evolution of tumor-promoting CAFs.
Abstract
p16
INK4a
(CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16
INK4a
accumulate in aging tissues and appear in premalignant lesions, ...yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16
INK4a
in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16
INK4a
expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16
INK4a
expression, and Wnt inhibition suppresses p16
INK4a
-induced hyperplasia. Senolytic treatment reduces p16
INK4a
-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16
INK4a
-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16
INK4a
expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.
Differentiation‐associated regulatory programs are central in determining tumor phenotype, and contribute to heterogeneity between tumors and between individual cells within them. The transcriptional ...programs that control luminal and basal lineage identity in the normal mammary epithelium, as well as progenitor and stem cell function, are active in breast cancers, and show distinct associations with different disease subtypes. Also active in some tumors is the epithelial to mesenchymal transition (EMT) program, which endows carcinoma cells with mesenchymal as well as stem cell traits. The differentiation state of breast cancer cells is thus dictated by the complex combination of regulatory programs, and these can dramatically affect tumor growth and metastatic capacity. Breast cancer differentiation is often viewed along an axis between a basal–mesenchymal–stem cell state and a luminal–epithelial–differentiated state. Here we consider the links, as well as the distinctions, between the three components of this axis: basal versus luminal, mesenchymal versus epithelial, and stem cell versus differentiated identity. Analysis on a multidimensional scale, in which each of these axes is assessed separately, may offer increased resolution of tumor differentiation state. Cancer cells possessing a high degree of stemness would display increased capacity to shift between positions on such a multidimensional scale, and to acquire intermediate phenotypes on its different axes. Further molecular analysis of breast cancer cells with a focus on single‐cell profiling, and the development of improved tools for dissection of the circuits controlling gene activity, are essential for the elucidation of the programs dictating breast cancer differentiation state. WIREs Syst Biol Med 2014, 6:93–106. doi: 10.1002/wsbm.1252
This article is categorized under:
Developmental Biology > Developmental Processes in Health and Disease
Developmental Biology > Lineages
Physiology > Mammalian Physiology in Health and Disease
Developmental Biology > Stem Cell Biology and Regeneration
Breast cancer subtypes display distinct biological traits that influence their clinical behavior and response to therapy. Recent studies have highlighted the importance of chromatin structure ...regulators in tumorigenesis. The RNF20-RNF40 E3 ubiquitin ligase complex monoubiquitylates histone H2B to generate H2Bub1, while the deubiquitinase (DUB) USP44 can remove this modification. We found that RNF20 and RNF40 expression and global H2Bub1 are relatively low, and USP44 expression is relatively high, in basal-like breast tumors compared with luminal tumors. Consistent with a tumor-suppressive role, silencing of RNF20 in basal-like breast cancer cells increased their proliferation and migration, and their tumorigenicity and metastatic capacity, partly through upregulation of inflammatory cytokines. In contrast, in luminal breast cancer cells, RNF20 silencing reduced proliferation, migration and tumorigenic and metastatic capacity, and compromised estrogen receptor transcriptional activity, indicating a tumor-promoting role. Notably, the effects of USP44 silencing on proliferation and migration in both cancer subtypes were opposite to those of RNF20 silencing. Hence, RNF20 and H2Bub1 have contrasting roles in distinct breast cancer subtypes, through differential regulation of key transcriptional programs underpinning the distinctive traits of each subtype.
p16
INK4a
(CDKN2A) is a central tumor-suppressor and activator of senescence. We recently found that prolonged expression of p16
INK4a
in epidermal cells induces hyperplasia and dysplasia through ...Wnt-mediated stimulation of neighboring keratinocytes. The study suggests a pro-tumorigenic function of p16
INK4a
in early epidermal lesions, which could potentially be targeted by senolytic therapy.
Regulatory factors controlling stem cell identity and self-renewal are often active in aggressive cancers and are thought to promote their growth and progression. TCF3 (also known as TCF7L1) is a ...member of the TCF/LEF transcription factor family that is central in regulating epidermal and embryonic stem cell identity. We found that TCF3 is highly expressed in poorly differentiated human breast cancers, preferentially of the basal-like subtype. This suggested that TCF3 is involved in the regulation of breast cancer cell differentiation state and tumorigenicity. Silencing of TCF3 dramatically decreased the ability of breast cancer cells to initiate tumor formation, and led to decreased tumor growth rates. In culture, TCF3 promotes the sphere formation capacity of breast cancer cells and their self-renewal. We found that in contrast to ES cells, where it represses Wnt-pathway target genes, TCF3 promotes the expression of a subset of Wnt-responsive genes in breast cancer cells while repressing another distinct target subset. In the normal mouse mammary gland, Tcf3 is highly expressed in terminal end buds, structures that lead duct development. Primary mammary cells are dependent on Tcf3 for mammosphere formation, and its overexpression in the developing gland disrupts ductal growth. Our results identify TCF3 as a central regulator of tumor growth and initiation, and a novel link between stem cells and cancer.
In normal human cells, telomeres shorten with successive rounds of cell division, and immortalization correlates with stabilization of telomere length. These observations suggest that human cancer ...cells achieve immortalization in large part through the illegitimate activation of telomerase expression. Here, we demonstrate that the rate-limiting telomerase catalytic subunit hTERT is expressed in cycling primary presenescent human fibroblasts, previously believed to lack hTERT expression and telomerase activity. Disruption of telomerase activity in normal human cells slows cell proliferation, restricts cell lifespan, and alters the maintenance of the 3′ single-stranded telomeric overhang without changing the rate of overall telomere shortening. Together, these observations support the view that telomerase and telomere structure are dynamically regulated in normal human cells and that telomere length alone is unlikely to trigger entry into replicative senescence.
PDF
