Paracrine roles of cellular senescence in promoting tumourigenesis

In the paper

“Furthermore, the SASP is involved in valuable physiological processes such as promoting tissue repair,18–20 fine-tuning the development of embryonic structures,21–23 and stimulating immune surveillance.24,25”

What the sources say

• Supported

  This citation is attached to the tissue-repair clause, not the separate claims about embryonic development or immune surveillance. The Results report that CCN1-induced senescence produces an antifibrotic program in cutaneous wounds, and the Introduction identifies secreted proteins involved in extracellular-matrix metabolism as part of the SASP. Together, these support a beneficial role for the senescent-cell secretory response in wound repair. (LLM, conf=0.88)

  cites [18] Jun, J. I. & Lau, L. F. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat. Cell Biol. 12, 676–685 (2010). source
• Supported

  This source is cited for the tissue-repair clause, not the separately cited claims about embryonic development or immune surveillance. The Introduction states that wound-associated senescent cells promote healing by secreting PDGF-A, a SASP factor; the Discussion explicitly describes a positive role for the SASP in tissue repair. Page numbers are not available in our copy. (LLM, conf=0.94)

  cites [19] Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell. 31, 722–733 (2014). source
• Supported

  The citation to this paper is attached to the immune-surveillance clause, not the tissue-repair or embryonic-development clauses. In the Results section, the paper reports that senescent activated stellate cells upregulate genes predicted to enhance immune surveillance; the Discussion links those factors to immune clearance. (LLM, conf=0.93)

  cites [20] Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). source
• Supported

  This source is cited for the embryonic-development part of the sentence, not the separate tissue-repair or immune-surveillance claims. The Discussion (p. 9) says that embryonic signaling centers instruct growth and patterning through secreted factors that are also SASP components; the Figure 7 caption (p. 8) describes senescence as instructing local tissue patterning. (LLM, conf=0.90)

  cites [21] Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013). source
• Partly supported

  The Clearance of Senescent Cells and Compensatory Mechanisms section reports that developmental senescence helps eliminate mesonephric tubules and establish the correct balance of cells in the embryonic endolymphatic sac. The Introduction describes how the SASP can promote tissue remodeling, but the paper does not establish that the SASP itself fine-tunes those embryonic structures. The tissue-repair and immune-surveillance clauses have separate citations and are not assessed here. (LLM, conf=0.82)

  cites [22] Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013). sourceExperimental — accuracy not yet measured
• Partly supported

  The citation to this paper is attached to the embryonic-development part of the sentence, not the tissue-repair or immune-surveillance parts. In the Discussion, the authors suggest that programmed senescence contributes to cement-gland organogenesis and adjacent tissue remodelling, but say it is only possible that a TGFβ-dependent secretory phenotype mediates those effects. The claim presents the SASP's developmental role more firmly than the paper does. (LLM, conf=0.87)

  cites [23] Davaapil, H., Brockes, J. P. & Yun, M. H. Conserved and novel functions of programmed cellular senescence during vertebrate development. Development 144, 106–114 (2017). sourceExperimental — accuracy not yet measured
• Supported

  The citation to this paper is attached to “stimulating immune surveillance,” not to tissue repair or embryonic development. The Abstract reports that senescent tumour cells upregulated immune-modulating signals and triggered an innate immune response that contributed to tumour clearance. (LLM, conf=0.90)

  cites [24] Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). source
• Not checked yetcites [25] Lujambio, A. To clear, or not to clear (senescent cells)? That is the question. Bioessays 38(Suppl. 1), S56–S64 (2016). source

In the paper

“Importantly, genetic or chemical ablation of senescent cells in mouse models delays the onset of age-related disorders, including cancer, leading to increased life-spans and promoting tissue rejuvenation in late life.36–38”

What the sources say

• Partly supported

  The Abstract reports that genetic clearance delayed several age-associated disorders in a progeroid mouse model, and that ABT263 cleared senescent cells and rejuvenated aged stem cells in mice. It does not report delayed cancer onset or increased lifespan; it describes extending health span as a prospect, not a demonstrated result. (LLM, conf=0.89)

  cites [36] Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016). sourceExperimental — accuracy not yet measured
• Partly supported

  The main text (Fig. 2) reports that drug-triggered clearance of p16Ink4a-positive cells in progeroid mice delayed selected age-related phenotypes. It does not report delayed cancer onset and explicitly says overall survival was not substantially extended (Supplementary Fig. 5d). The late-life analysis (Fig. 4) describes attenuated decline in muscle and fat rather than a reversal of ageing, so “tissue rejuvenation” overstates that result. (LLM, conf=0.90)

  cites [37] Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract and Discussion (page unavailable) report that clearing p16Ink4a-positive cells in mice extended median lifespan, delayed tumor progression, and slowed age-related deterioration in several organs. But this study used a drug to activate a genetically engineered cell-ablation system; it does not establish that chemical ablation alone has those effects. It reports preservation of tissue function after treatment beginning at midlife, not rejuvenation of already deteriorated tissue in late life. (LLM, conf=0.86)

  cites [38] Baker, D. J. et al. Naturallyoccurringp16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). sourceExperimental — accuracy not yet measured

In the paper

“The composition and intensity of the SASP response can be affected by several factors including the senescence-inducing mechanism, cell type, and the amount of time passed since senescence initiation, indicating that there is no singular SASP.12–17”

What the sources say

• Not checked yetcites [12] Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008). source
• Not checked yetcites [13] Maciel-Baron, L. A. et al. Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli. Age 38, 26 (2016). source
• Not checked yetcites [14] Coppe, J. P. et al. Tumor suppressor and agingbiomarkerp16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. J. Biol. Chem. 286, 36396–36403 (2011). source
• Not checked yetcites [15] Kipling, D. et al. A transcriptomic analysis of the EK1.Br strain of human fibroblastoid keratocytes: the effects of growth, quiescence and senescence. Exp. Eye Res. 88, 277–285 (2009). source
• Not checked yetcites [16] Hoare, M. et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat. Cell Biol. 18, 979–992 (2016). source
• Not checked yetcites [17] Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013). source

In the paper

“Activation of the senescence programme leads to cellular and molecular changes such as proliferation arrest, chromatin remodelling, elevated expression of cell cycle inhibitors (such as p16INK4A or p21CIP1), activation of a DNA damage response, enlargement of the lysosomal compartment, and activation of a senescence-associated secretory phenotype (SASP).5,6”

What the sources say

• Not checked yetcites [5] Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011). source
• Not checked yetcites [6] van Deursen, J. M. The role of senescent cells in ageing. Nature 509, 439–446 (2014). source

In the paper

“Senescence serves as a response to stress, and several inducing stimuli have now been identified including chemotherapeutic, radiation and oxidative stress, amongst others (Fig. 1).”

In the paper

“Supporting this notion, the burden of senescent cells in tissues increases significantly with age in mice, primates, and humans,27 and they can be found in both benign and malignant tumours.31–35”

What the sources say

• Not checked yetcites [31] Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005). source
• Not checked yetcites [32] Haugstetter, A. M. et al. Cellular senescence predicts treatment outcome in metastasised colorectal cancer. Br. J. Cancer 103, 505–509 (2010). source
• Not checked yetcites [33] Vizioli, M. G. et al. Evidence of oncogene-induced senescence in thyroid carcinogenesis. Endocr. Relat. Cancer 18, 743–757 (2011). source
• Not checked yetcites [34] Reimann, M. et al. Tumor stroma-derived TGF-beta limits myc-driven lymphomagenesis via Suv39h1-dependent senescence. Cancer Cell. 17, 262–272 (2010). source
• Not checked yetcites [35] Roberson, R. S., Kussick, S. J., Vallieres, E., Chen, S. Y. & Wu, D. Y. Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res. 65, 2795–2803 (2005). source

In the paper

“Senescence was traditionally considered an innate anti-cancer mechanism as it can serve to eliminate damaged cells,3,5 whereby activation of the senescence programme in cells harbouring oncogenic mutations serves as a tumour suppressor mechanism, preventing the expansion of these mutated cells and progression into malignancies.3,5”

What the sources say

• Not checked yetcites [3] He, S. & Sharpless, N. E. Senescence in health and disease. Cell 169, 1000–1011 (2017). source
• Not checked yetcites [5] Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011). source

In the paper

“Senescent cells can contribute to the acquisition of invasive and metastatic properties of cancer cells, as well as the induction of tumour-associated angiogenesis.7,39”

What the sources say

• Not checked yetcites [7] Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev. Pathol. 5, 99–118 (2010). source
• Not checked yetcites [39] Alspach, E., Fu, Y. & Stewart, S. A. Senescence and the pro-tumorigenic stroma. Crit. Rev. Oncog. 18, 549–558 (2013). source

In the paper

“Interestingly, the SASP is able to inhibit differentiation both in vitro and in vivo, while in some cases leads to acquisition of stem cell characteristics.41,44,54,55,64–66”

What the sources say

• Not checked yetcites [41] Parrinello, S., Coppe, J. P., Krtolica, A. & Campisi, J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J. Cell Sci. 118(Pt 3), 485–496 (2005). source
• Not checked yetcites [44] Tsai, K. K., Chuang, E. Y., Little, J. B. & Yuan, Z. M. Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment. Cancer Res. 65, 6734–6744 (2005). source
• Not checked yetcites [54] Ohanna, M. et al. Secretome from senescent melanoma engages the STAT3 pathway to favor reprogramming of naive melanoma towards a tumor-initiating cell phenotype. Oncotarget 4, 2212–2224 (2013). source
• Not checked yetcites [55] Canino, C. et al. SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells. Oncogene 31, 3148–3163 (2012). source
• Not checked yetcites [64] Cahu, J., Bustany, S. & Sola, B. Senescence-associated secretory phenotype favors the emergence of cancer stem-like cells. Cell Death Dis. 3, e446 (2012). source
• Not checked yetcites [65] Ritschka, B. et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 31, 172–183 (2017). source
• Not checked yetcites [66] Mosteiro, L. et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science 354, (2016). source

In the paper

“Exposure of keratinocytes to the culture medium from senescent cells promotes expression of tumour stem cell markers, such as CD44, and leads to a greater regenerative capacity in vivo. 65”

What the sources say

• Not checked yetcites [65] Ritschka, B. et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 31, 172–183 (2017). source

In the paper

“In addition, individual SASP components can contribute to induce EMT phenotypes; IL6, for example, has been shown to have cell-adhesion disrupting actions, which is an important component of invasion.56”

What the sources say

• Not checked yetcites [56] Tamm, I., Kikuchi, T., Cardinale, I. & Krueger, J. G. Cell-adhesion-disrupting action of interleukin 6 in human ductal breast carcinoma cells. Proc. Natl Acad. Sci. USA 91, 3329–3333 (1994). source

In the paper

“A large number of proangiogenic factors are also known to be secreted by senescent cells, whereas angiostatic molecules have not been found to be secreted.27,60”

What the sources say

• Not checked yetcites [27] Campisi, J. Aging, cellular senescence, and cancer. Annu Rev. Physiol. 75, 685–705 (2013). source
• Not checked yetcites [60] Oubaha, M. et al. Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci. Transl. Med. 8, 362ra144 (2016). source

In the paper

“These experiments collectively demonstrate that the SASP can promote cancer cell growth, challenging the view that senescence is primordially a beneficial process involved in preventing cancer progression.”

In the paper

“Furthermore, cellular reprogramming, which is the process by which adult differentiated cells can be induced to become functionally equivalent to embryonic stem cells, can be induced in vivo by senescent cells through SASP activation, and this can be stimulated in different models of tissue damage.”

In the paper

“Cells undergoing damage-induced senescence are often cleared by the immune system, as several SASP factors are cytokines and chemokines that can modulate the local immune environment.2,3,5,70,71”

What the sources say

• Not checked yetcites [2] Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014). source
• Not checked yetcites [3] He, S. & Sharpless, N. E. Senescence in health and disease. Cell 169, 1000–1011 (2017). source
• Not checked yetcites [5] Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011). source
• Not checked yetcites [70] Vicente, R., Mausset-Bonnefont, A. L., Jorgensen, C., Louis-Plence, P. & Brondello, J. M. Cellular senescence impact on immune cell fate and function. Aging Cell 15, 400–16 (2016). source
• Not checked yetcites [71] Velarde, M. C., Demaria, M. & Campisi, J. Senescent cells and their secretory phenotype as targets for cancer therapy. Interdiscip. Top. Gerontol. 38, 17–27 (2013). source

In the paper

“Furthermore, it was shown that this leads to the inhibition of anti-tumour T-cell responses and enhanced tumour growth.77”

What the sources say

• Not checked yetcites [77] Ruhland, M. K. et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat. Commun. 7, 11762 (2016). source

In the paper

“In this sense, a crucial role for the mechanistic target of rapamycin (mTOR) complex has recently been unveiled, whereby it can either counteract or facilitate reprogramming by cell-intrinsic and cell-extrinsic mechanisms, respectively.69”

What the sources say

• Not checked yetcites [69] Aarts, M. et al. Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence. Genes Dev. 31, 2085–2098 (2017). source

In the paper

“While senescence is a barrier to reprogramming in vitro, the paracrine activities of senescent cells can promote the expression of stem cell markers and proliferation of neighbouring cells in vivo, 66–68 and IL6 is a key player in driving this process.”

What the sources say

• Not checked yetcites [66] Mosteiro, L. et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science 354, (2016). source
• Not checked yetcites [67] Chiche, A. et al. Injury-induced senescence enables in vivo reprogramming in skeletal muscle. Cell. Stem Cell. 20, 407–14.e4 (2017). source
• Not checked yetcites [68] Mosteiro, L., Pantoja, C., de Martino, A. & Serrano, M. Senescence promotes in vivo reprogramming through p16(INK)(4a) and IL-6. Aging Cell (2017). PubMed PMID: 29280266. Epub 2017/12/28. eng. https://doi.org/10.1111/acel.12711 . source

In the paper

“Together, these data suggest that senescent cells, through their SASP, can induce undifferentiated cellular states; depending on the context, this can be beneficial (e.g. tissue regeneration) or harmful (e.g. promotion of tumour-initiating cells).”

In the paper

“Since senescent cells are generally abundant in benign tumours and also present at low numbers in several malignancies,31–34,57 their paracrine activities could contribute to tumour progression and cancer metastasis.”

What the sources say

• Not checked yetcites [31] Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005). source
• Not checked yetcites [32] Haugstetter, A. M. et al. Cellular senescence predicts treatment outcome in metastasised colorectal cancer. Br. J. Cancer 103, 505–509 (2010). source
• Not checked yetcites [33] Vizioli, M. G. et al. Evidence of oncogene-induced senescence in thyroid carcinogenesis. Endocr. Relat. Cancer 18, 743–757 (2011). source
• Not checked yetcites [34] Reimann, M. et al. Tumor stroma-derived TGF-beta limits myc-driven lymphomagenesis via Suv39h1-dependent senescence. Cancer Cell. 17, 262–272 (2010). source
• Not checked yetcites [57] Kim, Y. H. et al. Senescent tumor cells lead the collective invasion in thyroid cancer. Nat. Commun. 8, 15208 (2017).