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

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].

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-x_L

Controls mitochondrial membrane permeability

Bcl-x_L 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].

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].

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-x_L, 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-x_L 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].