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Table 1 Prognostic implications of OIS and TIS based on available ex and in vivo evidence of cancer patients with solid tumors according to cancer type and senescence trigger

From: Cellular senescence in cancer: clinical detection and prognostic implications

Malignancy

Sample specification

Senescence markera

Type of senescenceb

Prognostic implication

Reference

NSCLC

Resected NSCLC

Lipofuscin

CS

High expression associated with worse OS

[126]

p21WAF1/Cip1, cyclin E and Ki67

[127]

Resected NSCLC SCC

p21WAF1/Cip1

Positive expression associated with improved survival

[128]

Resected NSCLC AC / SCC

Reduced expression in stage III compared to stage I or II

NSCLC SCC

p16INK4a

High expression associated with improved OS

[129]

Resected NSCLC AC / SCC

Loss of expression associated with worse OS

[130]

macroH2A1.1

Low expression associated with worse DFS

[131]

Resected NSCLC AC

Tumoral senescence signature (lipofuscin, p16INK4a, p21WAF1/Cip1 and Ki67c)

Tumoral senescence signature associated with worse DFS and OS

[132]

Resected NSCLC AC / SCC / other histology

TIS: platinum-based CT with or without RT

Evidence of TIS as treatment outcome

NSCLC AC

Senescence-related gene signature: FOXM1, HJURP, PKM, PTTG1 and TACC3

CS

High expression associated with:

- disease progression and worse OS

- immune-suppressive and protumorigenic TME

- high expression of immune checkpoint genes and TMB levels

[133]

Senescence marker genes: VPS26A and LANCL1

High expression associated with decreased survival

[134]

NSCLC AC

Senescence marker genes: VAMP3, STX4 and ARMX3

High expression associated with increased survival

NSCLC AC / SCC

Senescence marker genes: NTAL, DEP1 and B2MG

High expression associated with mixed survival outcomes depending on histology

Resected NSCLC

SA-β-Gal and CDK1

TIS: CB/PTX

Expression demonstrates TIS as treatment outcome

[37]

SA-β-Gal

TIS: CB/PTX or CRTd

Expression associated with worse OS

[135]

NSCLC AC

CS gene score

CS

Lower CS gene score in primary tumors compared to adjacent normal solid tissue

[136]

NSCLC SCC

Malignant pleural mesothelioma

Resected MPM

SA-β-Gal, p21WAF1/Cip1 and PAI1 and mRNA p21WAF1/Cip1 and PAI1

TIS: platinum-based CT

- Increased expression after neoadjuvant CT

- Stable disease associated with PAI1 expression, time-to-progression and worse OS

[137]

Breast cancer

Breast cancer

Senescence marker gene panel: DEP1, NTAL, EBP50, STX4, VAMP3, ARMX3, B2MG, LANCL1, VPS26A and PLD3

CS

High expression associated with increased OS

[134]

CS gene score

Lower score in primary tumors compared to adjacent normal solid tissue

[136]

Resected primary invasive ductal carcinoma

p16INK4a and p53

Expression associated with worse DFS and OS

[138]

Resected breast cancer

p16INK4a

Overexpression associated with unfavorable prognostic indicators (high grading, negative estrogen receptor status, inverse progesterone receptor status and high Ki67 expression) and indicative of a more undifferentiated malignant phenotype

[139]

p21WAF1/Cip1 and p53

Low p21WAF1/Cip1 expression along with p53 overexpression associated with short DFS and OS, suggesting p53 overexpression reflects complete abrogation of p53 function

[140]

p21WAF1/Cip1

Expression associated with worse DFS and OS

[141,142,143]

Early breast cancer

uPA-PAI1

- High levels associated with worse DFS

- Patients with high levels benefit more strongly from adjuvant CT

[144, 145]

Resected triple negative breast cancer

macroH2A1.1 mRNA ratio

High ratio associated with worse DFS

[146]

Resected breast cancer

SA-β-Gal

TIS: CP/DOX/5-FU

Expression demonstrated TIS as treatment outcome

[147]

p21WAF1/Cip1, p27Kip1, p53 and cyclin D3

TIS: CP/MTX/5-FU or ECX/DOC

[148]

p21WAF1/Cip1, H3K9Me3 and lamin B1c

TIS: DOC/DOX/CP, PTX/DOX/CP, DOX/CP, DOC/CP, 5-FU/EPX/CP or 5-FU/EPX/CP followed by DOC

[149]

mRNA of p16INK4a, p21WAF1/Cip1 and CCNA1

TIS: EPX/CP

- High expression demonstrated TIS as treatment outcome

- Persistent senescent cells evaded immune clearance

[150]

Lipofuscin

CS

Expression present in TME

[151]

TIS: CTd

Cervical, uterine, UCEC and ovarian cancer

Normal cervical epithelium

p16INK4a, p21WAF1/Cip1, p15INK4a and p14ARF

OIS

Almost completely negative expression

[152, 153]

Cervical dysplastic and SCC

Overexpression

Normal cervical epithelium, CIN and cervical carcinoma

p21WAF1/Cip1

Higher expression in cervical carcinoma compared to normal cervical epithelium and CIN

[154]

Expression associated with advanced stage

[155]

Cervical AC

Expression associated with favorable prognosis

[156]

Cervical SCC

CS gene score

CS

Positively correlated with PD-L1 protein expression and T cell cytotoxicity

[136]

UCEC

Lower score in primary tumors compared to adjacent normal solid tissue

Resected pEOC

SA-β-Gal

Expression demonstrated spontaneous CS

[157]

p21WAF1/Cip1 and p53

Low p21WAF1/Cip1 expression along with p53 overexpression associated with higher recurrence rate, suggesting p53 overexpression reflects complete abrogation of p53 function

[158]

Resected HGSOC

SA-β-Gal and γH2AX

Higher expression in older patients

[159]

Resected OC

p53, p16INK4a and pRb

Negative or high p53, high p16INK4a and reduced pRb expression associated with worse OS

[160]

Primary OC

SA-β-Gal, p16INK4a, H1-β and Ki67c

Identification of senescent CAFs adjacent to epithelial ovarian cancer cells suggested to promote ovarian cancer tumorigenesis

[161]

Normal ovary, primary OC, metastasis of OC, recurrent OC

p21WAF1/Cip1

- Expression gradually increased from normal ovary through primary OC, metastasis of OC and recurrent OC

- Expression associated with decreased time-to-progression

[162]

Advanced-stage serous OC and suboptimally debulked OC

Senescence marker genes: VAMP3, ARMCX3 and B2MG

CS/TISd

High expression associated with decreased survival

[134]

Senescence marker genes: EBP50 and NTAL

High expression associated with increased survival

Resected HGSOC

p16INK4a and lamin B1c

TIS: CB/PTX

High expression associated with improved 5-year OS

[163]

Esophageal cancer

Precursor and ESCC lesions

Dec1

OIS

Expression demonstrated OIS as tumor-suppressive mechanism

[164]

Resected ESCC

Low expression:

- correlated with poor clinicopathological parameters (i.e., T-stage, lymph node metastasis and pathological TNM-stage)

- associated with worse DFS

p16INK4a, p21WAF1/Cip1, pRb, Bax protein and cyclin D1

Combined high expression and low cyclin D1 expression associated with improved OS

[165]

Normal tissue, precursor lesions and ESCC

p16INK4a, p14ARF and p15INK4b

Increased expression in ESCC and in poorly differentiated specimens with lymph node metastasis, suggesting involvement of CS in cancer progression

[166]

p21WAF1/Cip1

- Expression frequently found in precursor lesions and invasive ESCC compared to normal tissue

- High expression associated with worse OS in curatively treated ESCC

[167]

EC

Senescence gene signature: ADH1B, IL1A, SERPINE1, SPARC, EZH2 and TNFAIP2

Enriched senescence gene signature in noncancerous cells of TME associated with improved OS

[168]

ESCC

CS gene score

CS

Lower score in primary tumors compared to adjacent normal solid tissue

[136]

Gastric cancer

Resected gastric cancer

Senescence gene signature: ADH1B, IL1A, SERPINE1, SPARC, EZH2 and TNFAIP2

CS

Enriched senescence gene signature in noncancerous cells of TME associated with:

- improved DFS and OS

- related to MSI, higher TMB and improved benefit from immunotherapy

[168]

Senescore based on proteins ADH1B, IL1A, SERPINE1, SPARC, EZH2 and TNFAIP2

High-senescore protein expression associated with improved OS

Gastric AC

CS gene score

Lower score in primary tumors compared to adjacent normal solid tissue

[136]

Gastric cancer

p21WAF1/Cip1 and mRNA of p21WAF1/Cip1

Increased expression associated with improved OS

[169]

Primary gastric adenocarcinoma

p21WAF1/Cip1 and p53

Low p21WAF1/Cip1 expression along with p53 overexpression associated with more aggressive tumoral characteristics, higher recurrence rate and poorer survival, suggesting p53 overexpression reflects complete abrogation of p53 function

[170]

Colorectal cancer

KRAS and BRAF mutated benign serrated polyps

SA-β-Gal, p16INK4a and Ki67c

OIS

- Expression demonstrated OIS

- OIS increased with degree of dysplasia

[171, 172]

Colon adenoma

SA-β-Gal, p16INK4a, p53, HP1α, HP1γ, H3K9me3 and Ki67c

Expression demonstrated OIS as tumor-suppressive mechanism

[15,16,17]

Dysplastic aberrant crypt foci and adenomas

p21WAF1/Cip1

Lower expression suggesting dysregulated expression of cell-cycle controlling genes in tumorigenesis of CRC

[173]

Early invasive colorectal carcinoma

SA-β-Gal, p16INK4a, p53, HP1α, HP1γ, H3K9me3 and Ki67c

Reduced or lost expression demonstrated loss of OIS

[15, 17, 171, 172]

Resected primary CRC

p21WAF1/Cip1, NTAL, ARMCX3, EBP50 and γH2AX

CS

- Absent and extensive expression associated with negative prognosis, moderate expression with best prognosis

- Distance between senescent cells and CD8+ T cells and a higher % CD8+ T cells near senescent cells linked to increased DSS and PFS, suggesting tumor-suppressive potential of CS is determined by TME and immune cell-mediated elimination of senescent tumor cells

[174]

p16INK4a and Ki67c

- Intratumoral senescence (high p16INK4a and low Ki67) associated with reduced T cell infiltrates and low-grade inflammatory cell infiltrate

- Low p16INK4a expression associated with decreased survival

[175]

CRC

Senescence marker genes: VPS26A, ARMCX3 and B2MG

High expression associated with decreased survival

[134]

Senescence marker genes: NTAL

High expression associated with increased survival

Senescence gene signature: ADH1B, IL1A, SERPINE1, SPARC, EZH2 and TNFAIP2

Enriched senescence gene signature in noncancerous cells of TME associated with improved OS

[168]

Metastasized CRC

p-ERK, HP1γ and PAI1

TIS: 5-FU/leucovorin

- Expression demonstrated TIS

- TIS associated with longer PFS

[176]

Resected CRC

SA-β-Gal and

mRNA of p21WAF1/Cip1, p16INK4a and IL-8

TIS: 5-FU and concomitant RT

- Increased expression demonstrated TIS

- TIS increased rectal cancer invasiveness by upregulation of EMT related genes

[177]

CRC

p21WAF1/Cip1

TIS: bevacizumab-based CT

- Increased expression demonstrated TIS

- TIS associated with longer PFS

[178]

CRC AC

CS

Decreased expression associated with higher Dukes stage, metastasis and worse survival

[179]

CRC

Downregulation and negative expression associated with MSI

[180, 181]

Decreased expression associated with lymph node and/or liver metastasis and worse survival

[182, 183]

p53

Absent expression associated with MSI

[181]

CRC AC

CS gene score

Lower score in primary tumors compared to adjacent normal solid tissue

[136]

Rectal AC

Rectal cancer

p21WAF1/Cip1

TIS: concurrent CRT (5-FU alone or with OXP)

Increased expression demonstrated TIS of inflammatory CAFs with a pronounced stromal response

[184]

Senescence gene signature

PC caused by cancer of the appendix, colon, rectosigmoid or rectum

SA-β-Gal, p16INK4a, p21WAF1/Cip1, H3K9me3 and Ki67c

OIS

- Increased expression demonstrated that PC is characterized by senescent tumor cells, and showed features of stemness

- Low or absent SA-β-Gal expression in primary tumor and liver metastasis samples compared to high SA-β-Gal expression in PC samples, suggesting that the peritoneal cavity is a metastatic niche that induces senescence, whereas no signs of senescence induction within the metastatic environment of the liver

- Absent SA-β-Gal expression in TILs of primary tumor and liver metastasis samples compared to elevated SA-β-Gal expression in TILs of PC samples, suggesting that senescent PC cells induce senescence in TILs

[185]

Senescence-associated and SASP genes

Upregulated in PC compared to primary tumor samples, and have a distinct SASP, demonstrating that senescent PC with stem cell-like features express a unique SASP

Pancreatic cancer

Resected PanIN and PDAC

p16INK4a and Ki67c

OIS

High expression in low-grade PanINs, no expression in PDAC

[186]

p21WAF1/Cip1

Expression increased with increasing grade of malignancy, demonstrating that aberrant cell cycle regulatory genes may be important in early development and progression of PanIN

[187]

Precursor lesions (acinar to ductal metaplasia), PanINs and PDAC

SA-β-Gal

Expression only in precursor lesions (acinar to ductal metaplasia) and PanINs, no expression in PDAC

[188]

Normal pancreas, pancreatitis and PDAC

SIN3B

- Absent or low expression in control pancreas and PDAC

- Strong expression in pancreatitis and PanINs and correlated with IL-1α

[189]

Hepatocellular carcinoma

Cirrhosis, dysplasia and HCC

Senescence-related genes: FAM38D, ATAD2, TOP2A, CCNE2, CRNDE, EPCAM, TMEM27, TFPI2, FOS, NAT2, GPR128, CYP39A1, FAM134B, SDCBP2 and MUM1L1

CS

Increased expression in liver cirrhosis, dysplasia being a transitional state to HCC and HCC that displayed immortal gene expression phenotypes

[190]

Chronic hepatitis C and cirrhosis

SA-β-Gal

Expression correlated with fibrosis progression in cirrhosis and chronic hepatitis C, suggesting CS predispose to HCC development

[191, 192]

p21WAF1/Cip1

Expression higher in cirrhosis compared to chronic hepatitis and associated with HCC development, suggesting p21WAF1/Cip1-related tumorigenesis in HCC

[193]

Biliary cirrhosis

p21WAF1/Cip1/Ki67c ratio

Increased expression ratios

[194]

Cirrhosis and HCC

p21WAF1/Cip1 and p16INK4a

Increased expression in cirrhosis, strongly reduced in HCC

[195]

Normal, chronic hepatitis C and HCC

SA-β-Gal

- Expression gradually increased from normal through chronic hepatitis C samples and HCC

- Expression in non-tumoral liver tissue correlated with HCC in surrounding liver

[192]

HCC

CS gene score

Lower score in primary tumors compared to adjacent normal solid tissue

[136]

Peritumoral HCC tissue

Senescence-related gene signature: FAM38D, ATAD2, TOP2A, CCNE2, CRNDE, EPCAM, TMEM27, TFPI2, FOS, NAT2, GPR128, CYP39A1, FAM134B, SDCBP2 and MUM1L1

OIS

Presence associated with:

- early recurrence and poor survival

- associated with chemokine (CCL2, CCL5 and CXCL11) and myeloid-specific gene expression and depletion in NK cell-specific gene activity

[196]

p16INK4a and p21WAF1/Cip1

Expression correlated with increased presence of CCR2 + myeloid cells

HCC

Senescence-related genes: LRP4, OPRK1, PRAC2, N4BP3, GAL, CORO2B, FZD7, SEPTIN3, SMOX, EPO, MSC, GLP1R, HOXC6, PAPPA2, STK39, DLGAP5, THEM64, UNC5B, SLC16A11, CDH1, PRR15L, CCDC146, FAM117A, SLC2A4, CD2 and STAT4

High senescence score:

- negatively correlated with the infiltration level of immunostimulating cells (plasma cells, CD8 T cells, activated CD4 memory T cells, gamma delta T cells and M1 macrophages) and positively correlated with the infiltration of immune-suppressive cells (memory B cells, naive CD4 T cells, M0 macrophages, M2 macrophages and eosinophils)

- negatively correlated with the expression levels of immune checkpoint related genes (i.e., CD274, LAG3, PDCD1L,

SIGLE and TIFIT) and lower response rate to immunotherapy

- related to immune dessert subtype of HCC

- associated with worse survival

[197]

Senescence marker protein 30

- Decreased expression in adjacent non-tumor tissue, larger tumor size and enhanced TMN-stage

- Decreased expression associated with worse OS

[198]

Cholangiocarcinoma

Premalignant bile duct adenomas, ductular reactions and CCA

p16INK4a

OIS

Expression in most premalignant bile duct adenomas and ductular reactions whereas barely expression in CCA, demonstrating OIS as tumor-suppressive mechanism

[199,200,201]

CCA

CS gene score

CS

Lower score in primary tumors compared to adjacent normal solid tissue

[136]

Prostate cancer

Prostate IN

SA-β-Gal and CXCR2

CS

Expression demonstrates CS as tumor-suppressive mechanism

[122]

BPH and prostate IN

SA-β-Gal, HP1α and HP1γ

[14, 18]

Primary prostate cancer

GLB1

Expression associated with:

- favorable clinicopathologic features (T stage and non-metastatic samples)

- improved prostate specific antigen-free survival

[202]

Resected prostate cancer

TIS: ADTd

Increased expression in tissues undergoing ADT longer than 5 months and in clinically more favorable intermediate grade cancers, demonstrating TIS as treatment outcome

[203]

GLB1, HP1γ and Ki67c

Increased expression suggests TIS might be responsible for incomplete tumor regression

[204]

mRNA of p16INK4a and p21WAF1/Cip1

TIS: MIT

Increased expression and expression of a SASP (increased mRNA levels encoding IL-6, IL-8, GM-CSF, GRO-α, IGFBP-2, and IL-1β), demonstrating TIS with SASP expression as treatment outcome

[73]

mRNA of p16INK4a, p21WAF1/Cip1 and CCNA1

TIS: MIT and MIT/DOC

- High expression demonstrated TIS as treatment outcome

- Persistent senescent cells evaded immune clearance

[150]

p21WAF1/Cip1

CS

Increased expression associated with high Gleason score and worse survival

[205, 206]

TIS: ADTd

- Increased expression associated with p53 accumulation after ADT, suggesting TIS as treatment outcome

- Increased expression associated with worse survival

[206]

Prostate AC

CS gene score

CS

- Lower score in primary tumors compared to adjacent normal solid tissue

- Positively correlated with PD-L1 protein expression and T cell cytotoxicity

- High score associated with improved PFS and OS

- Lower score associated with higher Gleason score, T and N stages

- Predicted active immune response and better prognosis

[136]

Bladder cancer

Precancerous and cancerous urinary bladder

p16INK4a, HP1α, HP1γ and H3K9me3

OIS

Expression demonstrated OIS as tumor-suppressive mechanism in precancerous and cancerous lesions

[17]

Radical cystectomy or transurethral resection

p16INK4a, p21WAF1/Cip1, p53 and pRb

Aberrant individual and/or combined expression associated with recurrence and worse OS

[207]

Transitional cell carcinoma

p21WAF1/Cip1

- Expression associated with worse DFS and OS in superficial lesions

- Loss of expression associated with worse DFS and OS in invasive lesions when accompanied by p53 accumulation

[208]

Bladder urothelial carcinoma

CS gene score

CS

Lower score in primary tumors compared to adjacent normal solid tissue

[136]

Skin cancer

Human benign naevi

SA-β-Gal and p16INK4a

OIS

Increased expression demonstrated p16INK4a-dependent OIS as tumor-suppressive mechanism

[13, 209]

Dermal neurofibroma

[210]

Dysplastic naevi and radial early melanoma

p16INK4a, p53 and p21WAF1/Cip1

Less p16INK4a expression and some p53 and p21WAF1/Cip1 expression demonstrated p53-dependent OIS as tumor-suppressive mechanism

[209]

Advanced melanoma

No p16INK4a and p21WAF1/Cip1 expression in advanced melanomas demonstrated escape from p16INK4a-dependent and/or p53-dependent OIS

Benign melanocytic and dysplastic naevi, in situ, invasive and metastatic melanoma

p16INK4a

Expression gradually decreased with increasing grade of malignancy

[211, 212]

Primary melanoma

No association with DFS or OS

[212]

Cutaneous malignant melanoma

Loss of expression correlated with tumor cell proliferation, thicker lesions and invasive stage

[213, 214]

Vertical growth phase melanoma

Loss of expression associated increased tumor cell proliferation and poor prognosis

[215]

Aggressive nodular malignant melanoma

Loss of expression associated with recurrent disease

[216]

Melanoma

CS gene score

CS

- Positively correlated with PD-L1 protein expression and T cell cytotoxicity

- Exhibited higher AUCs than the TIDE score for predicting immunotherapy response

[136]

Basal cell carcinoma

CS gene scores of malignant cells from non-responders significantly decreased after treatment whereas posttreatment CS scores significantly increased in ICB responders

Merkel cell carcinoma

Thyroid cancer

Early-stage papillary thyroid microcarcinoma, PTC and anaplastic thyroid carcinoma

p16INK4a, p21WAF1/Cip1 and IGFBP7

OIS

Expression gradually decreased with increasing grade of malignancy indicating involvement of OIS in thyroid carcinogenesis

[217]

V600EBRAF PTC

SA-β-Gal and p16INK4a

Expression next to proliferating cancer cells demonstrating OIS and cells escaping from OIS co-exist in V600EBRAF PTC

[218]

(V600EBRAF) PTC

SA-β-Gal, p16INK4a, and Ki67c and mRNA of p16INK4a

- Senescent tumor cells frequently present at invasive borders with features of collective invasion and high invasive ability with expression of a SASP

- Senescent tumor cells existed during lymphovascular invasion and metastasis

- Increased expression of CXCL12 in presence of senescent tumor cells in collective invasion area and diffuse CXCR4 expression in all PTC, demonstrating senescent tumor cell involvement in collective invasion and metastasis of PTC

[219]

Bone and soft tissue tumors

High grade sarcoma

p16INK4a

OIS

Decreased expression

[220]

Dedifferentiated liposarcoma, synovial sarcoma and leiomyosarcoma

Decreased expression associated with reduced survival indicating p16INK4a-dependent OIS as tumor-suppressive mechanism

Liposarcoma

Senescence marker genes: VPS26A and VAMP3

High expression associated with increased survival

[134]

Senescence marker genes: STX4

High expression associated with decreased survival

Osteosarcoma

Aging-/senescence-induced gene risk score

High score associated with:

- worse OS

- higher copy number variation score, implying a higher degree of tumor cell malignancy

- immune cold tumors: lack of innate immune activation of infiltrating immune cells, less infiltration of antigen presenting cells, high TIDE score and T cell rejection

- higher exhaustion and T cell proliferation scores

- enriched MIF, CLEC and VEGF signaling pathway which are involved in osteosarcoma growth and metastasis and blood vessel growth

[221]

Renal cell carcinoma

Primary RCC

p400

OIS

Decreased expression associated with advanced tumor stage, higher grade of malignancy, regional lymph node metastasis and poor prognosis

[222]

RCC

SA-β-Gal, p53, Dec1, Ki67c and Raf-1c

TIS: sunitinib

Increased expression demonstrates TIS as treatment outcome

[223]

CS gene score

CS

- Lower score in primary tumors compared to adjacent normal solid tissue

- Exhibited higher AUCs than the TIDE score for predicting immunotherapy response

[136]

KIRP

Brain malignancies

PA

SA-β-Gal, p16INK4a, p53 and Ki67c

OIS

Identification of OIS responsible for slow growth pattern, lack of progression to higher-grade tumors and high OS

[224]

Senescence-associated genes: CDKN2A, CDKN1A, CEBPB, GADD45A, and IGFBP7

SASP factors: FGF2, IL-15, CSF3, VEGFA, IL-17A, CCL2, CXCL8, CSF2, CCL3, IFNγ, IL-6, IL-13, CCL11 and IL-1β

High expression and upregulation of SASP associated with favorable PFS, demonstrating OIS is regulated by SASP

[225]

High-grade tumors and adult LGG

CDKN2A and TP53

Homogeneous deletion of CDKN2A and secondary alterations of CDKN2A and TP53 more common

[226,227,228]

IDH-mutant and lower grade (WHO grade II-III) astrocytoma

Absence of mutations associated with increased survival

[229, 230]

ACP

p21WAF1/Cip1, p53, GLB1, γH2AX, phosphor-DNA-PKc and Ki67c

Identification of senescent cells harboring molecular signature of OIS and SASP, demonstrating OIS and SASP drive cell transformation and tumor initiation

[231]

SASP factors: IL-1β, IL-6, IL-8, IL-10, IL-18, TNFα and IFNγ

Identification of SASP, demonstrating OIS and SASP drive cell transformation and tumor initiation

[232]

Medulloblastoma

CDKN2A and p53 pathway

Frequent CDKN2A promoter methylation and p53 pathway mutations, demonstrating OIS escape underlies tumor progression

[233,234,235]

Low-grade diffuse astrocytoma

p16INK4a and pRb

Loss of expression associated with shorter survival

[236]

Glioma

Senescence score based on senescence-associated genes: CCL2, CCL7, CDKN1A, COPG, CSF2RB, CXCL1, ICAM-1, IGFBP-3, IL-6, IL-8, SAA4, TNFRSF-11B, TNFSF-11 and TP53

CS

Senescence score:

- associated with poor prognosis

- correlated with older age

- increases with WHO histological grade (lowest values for low-grade astrocytomas (WHO II), higher values for anaplastic astrocytomas (WHO III) and highest values for glioblastomas (WHO IV) and gliosarcomas), linking senescence-associated gene signature to disease progression

[237]

SA-β-Gal and Ki67c

Identification of senescent cells

[238]

Senescence gene signature: ANXA5, APOE, CD151, CDKN1A, CDKN2A, CDKN2B, CTSB, CTSD, CTSL, CTSZ, EMP3, FTH1, LFITM3, LGFBP2, LGFBP3, LAMP1, LAMP2, LGALS1, MT1, OCIAD2, PDLIM4, RBP1, S100A11, SEP11, SDC4, SPARC, TIMP1, TM4SF1, TMSB4X, TNC and TNFRSF12A

Senescence gene signature associated with shorter survival

Normal and reactive brain tissue and glioma

p21WAF1/Cip1

Increased expression in glioma compared to normal and reactive brain tissue, suggesting p21WAF1/Cip1-related tumorigenesis in glioma

[239]

Astrocytic glioma

Expression associated with worse DFS

[240]

Astrocytic and high-grade glioma

Senescence marker genes: NTAL and STX

High expression associated with decreased survival

[134]

Astrocytic and high-grade glioma and glioblastoma

Senescence marker genes: VPS26A, ARMCX3 and B2MG

High expression associated with increased survival

Glioblastoma multiforme

CS gene score

CS

Positively correlated with PD-L1 protein expression and T cell cytotoxicity

[136]

Head and neck cancer

Oropharyngeal SCC

p16INK4a

OIS

Expression associated with favorable prognosis regardless of HPV status

[241]

Laryngeal, hypopharyngeal or oral SCC

No prognostic value

[242]

Normal, benign hyperplastic skin and oral lesions

Negative expression

[243, 244]

dysplastic and carcinoma in situ skin and oral SCC

Heterogeneous expression

Advanced skin and oral SCC

Consistent expression at areas of microinvasion and at superficial margins

deeply invasive skin and oral SCC

Near to complete absent expression, demonstrating p16INK4a-dependent OIS as tumor-suppressive mechanism

Oral SCC

p16INK4a, p53, pRb and cyclin D1

- Loss of p16INK4a expression earliest event in tumorigenesis

- Deregulation of pRb and p53 associated with malignant transformation and adverse prognosis

[245]

Premalignant dysplastic and SCC of skin and oral epithelium and HNSCC

CDKN2A

High frequency of gene mutation, deletion and promoter silencing

[243, 246]

HNSCC

H3K9Me

- Identification of senescent cells in 67.1% of biopsies

- More senescent cells in tumor center compared to invasive front

- No prognostic impact

[247]

Senescence score based on senescence-associated genes: DUSP16, EHF, ITSN2, DUSP3, HDAC4, TXNIP, KL, MAP4KI, PIK3R5, YPEL3, CDKN2A, MAP2K7, PIAS4, POU5F1, EZH2, DGCR8, TYK2, BTG3, SOCS1, G6PD, TXN, DPY30, AURKA, PDCD10, PSMD14, FXR1, PCGF2, GAPDH, PSMB5, RSL1D1, IL1A, CDK6, LIMA1, CAV1, SERPINE1, HSPA5, NEK6, ASPH, MAP2K1, ACLY, TOP1

High-senescence score:

- associated with worse OS

- correlated to poor clinicopathological parameters (histologic grade, TNM-stage, T-stage and lymph node metastasis)

[248]

Pharyngeal and laryngeal HNSCC

p21WAF1/Cip1

High expression associated with poor OS

[249]

Oral SCC

[250]

Tonsillar SCC

Expression associated with favorable DSS

[251]

Laryngeal and oral HNSCC

Higher expression associated with improved OS in stage III patients

[252]

Minor salivary gland adenoid cystic carcinoma

p16INK4a and p21WAF1/Cip1

CS

Strong and intense p21WAF1/Cip1 expression and complete negative p16INK4a expression, suggesting transient senescence insufficient to maintain the senescence-associated cell cycle arrest, avoiding cell death by senescence and favoring tumor growth

[253]

HNSCC

H3K9Me

TIS: RT with or without 5-FU/CP or 5-FU/CB

- Less senescent cells in post-RCT samples

- No prognostic impact

[247]

mRNA of CXCR2 receptor and/or its ligands (CXCL1–3, CXCL5, CXCL7, and CXCL8)

TIS: CRTd

Increased expression associated with impaired DSS, demonstrating TIS and SASP production determines radioresistance

[254]

CS gene score

CS

Lower score in primary tumors compared to adjacent normal solid tissue

[136]

Thymic cancer

Thymic cancer

CS gene score

CS

Positively correlated with PD-L1 protein expression and T cell cytotoxicity

[136]

  1. adetected by immunohistochemistry unless otherwise specified
  2. bdefined as CS unless otherwise specified
  3. cnegative marker of senescence
  4. dnot further specified
  5. 5-FU 5-fluorouracil, AC Adenocarcinoma, ACP Adamantinomatous craniopharyngioma, ADT Androgen deprivation therapy, AUCs Areas under the curve, BPH Benign prostate hypertrophy, CAFs Cancer-associated fibroblasts, CB Carboplatin, CCA Cholangiocarcinoma, CIN Cervical intraepithelial neoplasia, CLEC C-type lectin-like, CP Cisplatin, CP Cyclophosphamide, CRC Colorectal cancer, CRT chemoradiotherapy, CS Cellular senescence, CT chemotherapy, DFS Disease-free survival, DOC Docetaxel, DOX Doxorubicin, DSS Disease-specific survival, EC Esophageal cancer, ECM Extracellular matrix, ECX Epirubicin, EMT Epithelial-mesenchymal transition, ESCC Esophageal squamous cell cancer, HCC Hepatocellular carcinoma, HGSOC High-grade serous ovarian cancer, HNSCC Head and neck squamous cell carcinoma, ICB Immune-checkpoint blockade, IN intraepithelial neoplasia, KIRP Kidney renal papillary carcinoma, LLG Low-grade glioma, MIF Macrophage migration inhibitory factor, MIT Mitoxantrone, MPM Malignant pleural mesothelioma, MSI Microsatellite instability, MTX Methotrexate, NSCLC Non-small cell lung cancer, OC Ovarian cancer, OIS Oncogene-induced senescence, OS Overall survival, OXP Oxaliplatin, PA Pilocytic astrocytoma, PanIN Pancreatic intraepithelial neoplasia, PC Peritoneal cancer, PD-L1 Programmed death-ligand 1, PDAC Pancreatic ductal adenocarcinoma, pEOC Primary epithelial ovarian cancer, PFS Progression-free survival, pRb Retinoblastoma protein, PTC Papillary thyroid cancer, PTX pPaclitaxel, RCC Renal cell carcinoma, RCT Radiochemotherapy, RT Radiotherapy, SASP Senescence-associated secretory phenotype, SCC Squamous cell carcinoma, SS Senescence signature, TIDE Tumor immune dysfunction and exclusion, TILs Tumor-infiltrating lymphocytes, TIS Therapy-induced senescence, TMB Tumor mutational burden, TME Tumor microenvironment, UCEC Uterine corpus endometrial carcinoma, VEGF Vascular endothelial growth factor, WHO World Health Organization