It is clear that tumor cells can potentially utilize multiple mechanisms to evade apoptosis; however, several frequently employed pathways have been identified. Perturbation of the action of ligands of the tumor necrosis family (TNF), FasL, and TRAIL have been particularly studied in this context. FasL is a transmembrane protein that can trigger apoptosis in cells expressing its receptor Fas (CD95/APO-1). De novo expression of FasL by tumors, including colon, gastric, and lung carcinomas, is proposed to mediate immune privilege by inducing apoptosis in antitumor lymphocytes that express Fas. FasL -expressing colorectal and gastric tumors were characterized by increased numbers of apoptotic tumor-infiltrating lymphocytes (TIL).199,201 The ability of tumor-expressed FasL to suppress the immune response has been extensively verified experimentally.202 In addition, increased FasL expression accompanies disease progression in colorectal carcinoma and has been significantly associated with the probability of breast and cervical carcinomas to form lymph node metastasis.197,203 In an analogous fashion, upregulation of TRAIL has been observed in hepatocellular carcinoma, and its expression in gastric carcinoma is correlated with metastasis and the presence of apoptotic TIL.204,205
One necessary consequence of increased FasL or TRAIL levels is that tumors themselves need to develop resistance to their apoptotic effects. FasL resistance commonly occurs via decreased cell surface levels of Fas expression or expression of an antagonistic decoy receptor.197 Alternatively, upregulation of intracellular inhibitors of the proapoptotic pathway, such as cFLIP (FLICE inhibitory protein), IAP, or Bcl-2 and Bcl-XL has been documented (see above). Evading apoptosis is also relevant at the site of arrest, particularly in tissues that express high levels of TNF ligands, such as the lung and lymph nodes.198,206,207 In animal models, Fas expression inversely correlates with the capacity of cells to metastasize to the lung, as normally nonmetastatic cells (with high Fas levels) induce as many metastases as
subclones that express lower levels of Fas when injected into mice lacking FasL. , In patients, mutations in the Fas pathway, identified in NSCLC, significantly correlated with development of lymph node metastases.209 TRAIL knockout mice have also been shown to be more susceptible to development of metastases, while administration of TRAIL, or agonistic antibodies that activate its cognate receptors DR4 and DR5 suppress the formation of metastases.210,211-213 Consistently, mutations of DR4 and DR5 were found to be significantly associated with highly metastatic breast cancers.214 Mutations appear to be relatively rare, however, and other mechanisms, such as deficient DR transport to the cell surface or abrogation of the intracellular apoptosis inducing pathways (described above), may be more common. DAP kinase (DAPK), a serine threonine kinase involved in mediating FasL and TRAIL proapoptotic signals, has been linked to metastases in several studies. Aberrant methylation of DAPK has been associated with clinical aggressiveness of NSCLC, colon, bladder, and breast carcinoma and with development of lymph node metastasis in head and neck squamous cell carcinoma (HNSCC). Restoration of DAPK activity to highly metastatic cell lines reduced their capacity to metastasize to mouse lungs.216,217
Cells that do not die either remain dormant or begin to proliferate to form microscopic metastasis extra- or intravascularly. Dormant solitary cancer cells have been observed in experimental models and cancer patients and may be responsible for the recurrence of cancer due to their resistance to chemotherapeutic agents.216,218 In order to form occult metastasis, dormant cells must start to proliferate, maintain growth, and become vascularized. Experimental studies have suggested that each of these steps is inefficient, with only a fraction of cells surviving each stage.
Studies undertaken to establish the factors that maintain tumor cells in a dormant state have led to the identification of metastasis suppressors. The first metastasis suppressor, NM23, was identified in 1988; however, eight more have since been identified.216,219 Most were identified based on differential expression in metastatic and nonmetastatic cell lines and appear to act at discrete stages in the process of metastatic colonization. Exogenous expression of NM23 impairs motility and the metastatic potential of diverse cell lines in vivo but does not affect proliferation or primary tumor size.220 NM23 possesses histidine kinase activity that is essential for its metastasis suppressor activity.221 Kinase suppressor of RAS(KSR), a ERK-MAPK scaffold protein, binds and acts as a substrate for NM23. More recently, histidine phosphorylation has been shown to destabilize KSR leading to reduced extracellular signal regulated kinase (ERK) activation which was correlated with a reduction in metastatic capacity of a breast cancer cell line.222
KiSS-1 encodes a neuropeptide ligand for a GPCR hGPR54(AXOR12), identified as a gatekeeper of the reproductive cascade.223 KiSS-1 and hGPR54 display complementary expression patterns in the brain and in the placenta where they have been identified as regulators of trophoblast invasion, inducing migration and protease expression.224 KiSS-1 appears to play a similar role in tumor invasion and metastasis. Forced expression of KiSS-1 suppresses metastasis of melanomas and human breast carcinomas without affecting tumorigenicity.225-227 Although the action of Kiss-1 may depend on tumor type, loss of KiSS-1 expression was correlated with tumor recurrence in gastric cancer and venous invasion and distant metastasis in invasive bladder cancer patients. Additionally, loss of KiSS-1 and/or hGPR54 gene expression was found to be a significant predictor of lymph node metastasis in esophageal squamous cell carcinoma (ESCC).217
Upon entering the vasculature, mechanical forces contribute to the delivery of tumor cells to specific target organs. The relatively large size of solid tumor cells will tend to lead to their arrest in the first capillary bed they encounter. However, it apparent that tumors arising in particular organs have preferential secondary sites of metastasis, indicating that interaction between the cancer cells (seed) and the organ microenvironment (soil) can influence the fate of the cells.228 In addition to negative regulators, such as TNF ligand expression as described above, diverse factors that can promote the formation of tissue-specific metastasis have been postulated. Chemokines have been identified as key regulators of this process. Chemokines are soluble ligands that are involved in recognition and homing of multiple cell types, including hematopoietic cells, lymphocytes, and germ cells.229 Breast cancer cell lines, as well as carcinomas and metastasis, express high levels of the chemokine receptors CXCR4 and chemokine receptor 7(CCR7).230 The ligands for these receptors, stromal cell-derived factor-1, CCL19, and CCL21, are expressed in those tissues where breast cancers most often metastasize, such as lymph nodes, lung, liver, and bone marrow.231 Binding of SDF-1 to CXCR4 upregulates expression of proteases and adhesion molecules and enhances invasion and migration in vitro. Disruption of the receptor-ligand interaction was sufficient to inhibit spontaneous metastasis to the lung and lymph nodes.232-234 Similar studies have implicated CXCR4, as well as other chemokine receptor and ligand family members, in the metastatic behavior of other tumor types, including melanoma (CXCR4, CCR7, and CCR10), colorectal cancer (CXCR4 and CCR7), and prostate cancer (CXCR4 and CCR9).235 Notably, these agents frequently affect both tumor growth and invasiveness, suggesting CXCR4 may also function at the site of the primary tumor. A more recent publication has demonstrated that breast carcinoma-associated fibroblasts (CAF) express high levels of SDF-1. Expression of SDF-1 by CAF enhanced growth of tumors, via activation of CXCR4, and recruited endothelial cell precursors, promoting vascularization.236
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