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Table 1 Roles of the major known apoptotic participators in cancer metastasis

From: Apoptosis, autophagy, necroptosis, and cancer metastasis

Gene Description Association with cancer metastasis (representative examples)
1. Caspases and caspase inhibitors
Caspase-8 Initiator caspase Caspase-8 knockout Th-MYCN mice developed advanced neuroblastoma with bone marrow metastasis [22].
Caspase-10 Initiator caspase Caspase-10 mutations were identified in NSCLC patients with lymph node metastases [23].
Caspase-3 Effector caspase The caspase-3 protein level negatively correlated with lymph node metastasis in NSCLC patients [24]. Another report described an inverse association between caspase-3 expression and lymph node metastasis in gastric carcinomas, although most of the caspase-3 protein was not activated [25].
IAPs (XIAP, survivin, and cIAP1/2) Caspase inhibitors Increased levels of the apoptosis inhibitor protein XIAP contributed to the anoikis resistance of circulating human prostate cancer metastatic precursor cells [26]. A recent study showed that intermolecular cooperation between XIAP and survivin stimulated tumor cell invasion and promoted metastasis and that this pathway was independent of the IAP-mediated inhibition of cell death [27].
DAPK Upstream regulator of capases-3/6/7 DAPK downregulation or inactivation was observed in several metastatic cancers. In certain cases, DAPK downregulation correlated with metastatic recurrence [28].
2. Intrinsic apoptotic pathway
Apaf-1 Key apoptosome component Apaf-1 gene haploinsufficiency correlated with colorectal carcinoma progression and hepatic metastasis [29].
Bcl-2 Controls mitochondrial membrane permeability The pulmonary metastatic burden was dramatically augmented in mice inoculated with Bcl-2 transfectants [30]. Elevated nuclear expression of Bcl-2 correlated with increased hepatocellular carcinoma metastasis [31].
Bcl-xL Controls mitochondrial membrane permeability Bcl-xL overexpression caused apoptosis resistance and acted as an enhancer of metastasis but not primary tumor growth [32].
Bax Same as above Bax expression was markedly decreased in metastatic colorectal cancer cells [33]. Bax inhibitor-1 enhanced cancer metastasis [34].
Maspin Serine protease inhibitor Maspin expression was reduced in brain-metastasized breast cancer cells [35]. Decreased expression of maspin restricted the growth and metastasis of colorectal cancer xenografts in mice [36].
3. Extrinsic apoptotic pathway
FADD Key adaptor that transmits death signals mediated by death receptors Somatic mutations in FADD were observed at a higher frequency in metastatic NSCLC tumors than in the corresponding primary tumors [23]. High FADD expression was associated with regional and distant metastasis in squamous cell carcinoma of the head and neck [37].
FasL and Fas Key death ligand and its receptor, respectively Fas-sensitive melanoma clones were highly tumorigenic but were rarely metastatic in wild-type syngeneic mice. However, in FasL-deficient mice, both the incidence and the number of metastases were increased [38]. The ability of osteosarcoma cells to form lung metastases inversely correlated with cell surface Fas expression [39].
sFas and DcR3 soluble Fas and FasL decoy receptor, respectively In gastric carcinomas, the serum DcR3 levels closely correlated with the tumor differentiation status and the TNM classification [40].
TRAIL TNF family death ligand Mice depleted of NK cells or treated with a TRAIL-blocking antibody exhibited a significant increase in spontaneous liver metastasis [41,42].
DR4 and DR5 Death receptors for TRAIL TRAIL receptor deficiency in mice enhanced lymph node metastasis of squamous cell carcinoma without affecting primary tumor development [43].
DcR1, DcR2, and OPG TRAIL decoy receptors The expression of decoy receptors in tumor cells served as an alternate mechanism to resist TRAIL-induced apoptosis [42].
4. Regulators of apoptotic pathways
JNKs Dual-role regulators of apoptosis JNKs induced or inhibited cancer cell apoptosis in a manner that was dependent on the cell type, the stimulus, the duration of JNK activation and the activity of other pathways [44]. JNKs served dual roles as both suppressors and promoters of cancer metastasis [45-47].
NF-κB Transcription factor Activated NF-κB transactivated many anti-apoptotic genes, including Bcl-2, Bcl-xL, survivin, cIAP-1/2, and c-FLIP, as well as many angiogenesis-related genes [48]. NF-κB activity was closely associated with cancer metastasis [49,50].
p53 and p63 Transcription factors p53 upregulated pro-apoptotic genes, such as Fas, DR5, Bax, Bak and Apaf-1, and repressed anti-apoptotic effectors, such as Bcl-2, Bcl-xL and survivin [51]. p53 loss or mutation promoted tumor metastasis [44]. The loss of p53 led to invasion and lymph node metastasis of carcinogen-induced colorectal tumors [52]. By interacting with mutant p53, p63 suppressed tumorigenesis and metastasis [53,54].
TGF-β, TβRI/II, and SMADs TGF-β pathway genes The SMAD complex transactivated a series of apoptosis-related genes [55-58]. TGF-β signals also induced apoptosis via the activation of the ARTS and Daxx-JNK pathways [59,60]. Prior to tumor initiation and the early stages of progression, TGF-β signaling acted as a tumor suppressor; however, at later stages, it often promoted metastasis [61].
MMPs Prominent family of proteinases MMPs played roles in the regulation of ECM turnover, cancer cell migration, cell growth, inflammation, and angiogenesis [62]. They also interfered with the induction of apoptosis in malignant cells via the cleavage of ligands or receptors in the apoptotic pathways [63-65].
  1. Note: NSCLC, non-small-cell lung cancer; Apaf-1, apoptotic protease-activating factor; IAPs, cellular inhibitors of apoptosis proteins; XIAP, X-linked inhibitor of apoptosis; DAPK, death-associated protein kinase; FADD, Fas-associated death domain-containing protein; sFas, soluble Fas; DcR3, decoy receptor 3; TRAIL, TNF-related apoptosis-inducing ligand; DcR1, decoy receptor 1, also referred to as TRAIL-R3; DcR2, decoy receptor 2, also referred to as TRAIL-R4; OPG, osteoprotegerin; DR4, death receptor 4; TβR I/II, TGF-β receptor I/II; MMPs, matrix metalloproteinases; JNK, c-Jun N-terminal kinases.