Another open question is whether there are genes whose principal or sole contribution is to control programs of gene expression that promote metastasis. This question is of more than academic interest, because if altered forms of certain genes promote or suppress the metastatic phenotype, their detection in a primary tumor would have both prognostic and therapeutic implications. Among candidates for such metastasis oncogenes are those encoding SNAIL and TWIST, transcription factors whose primary function is to promote epithelial-to-mesenchymal transition (EMT). In EMT, carcinoma cells downregulate certain epithelial markers (e.g., E-cadherin) and upregulate certain mesenchymal markers (e.g., vimentin, smooth muscle actin). These molecular changes are accompanied by phenotypic alterations such as morphologic change from polygonal epithelioid cell shape to a spindly mesenchymal shape, along with increased production of proteolytic enzymes that promote migration and invasion. These changes are believed to favor the development of a promigratory phenotype that is essential for metastasis. Loss of E-cadherin expression seems to be a key event in EMT, and SNAIL and TWIST are transcriptional repressors that downregulate E-cadherin expression. How expression of these master regulator transcription factors is stimulated in tumors is not clear; however, experimental models suggest that interactions of tumor cells with stromal cells are a key stimulus for this change. Thus, acquisition of a metastatic phenotype may not require a set of mutations but may be an emergent property arising from the interactions of tumor cells and stroma.
Abilitytoinvadetissues,ahallmarkofmalignancy,occursinfoursteps:looseningofcell–cellcontacts,degradationofECM,attachmenttonovelECMcomponents,andmigrationoftumorcells.
Cell–cellcontactsarelostbytheinactivationofE-cadherinthroughavarietyofpathways.
Basementmembraneandinterstitialmatrixdegradationismediatedbyproteolyticenzymessecretedbytumorcellsandstromalcells,suchasMMPsandcathepsins.
ProteolyticenzymesalsoreleasegrowthfactorssequesteredintheECMandgeneratechemotacticandangiogenicfragmentsfromcleavageofECMglycoproteins.
Themetastaticsiteofmanytumorscanbepredictedbythelocationoftheprimarytumor.Manytumorsarrestinthefirstcapillarybedtheyencounter(lungandliver,mostcommonly).
Sometumorsshoworgantropism,probablyduetoactivationofadhesionorchemokinereceptorswhoseligandsareexpressedbyendothelialcellsatthemetastaticsite.
Long one of the “holy grails” of oncology, the promise of therapies that enable the host immune system to recognize and destroy cancer cells is finally coming to fruition, largely due to a clearer understanding of the mechanisms by which cancer cells evade the host response. Paul Ehrlich first conceived the idea that tumor cells can be recognized as “foreign” and eliminated by the immune system. Subsequently, Lewis Thomas and Macfarlane Burnet formalized this concept by coining the term immune surveillance, based on the premise that a normal function of the immune system is to constantly “scan” the body for emerging malignant cells and destroy them. This idea has been supported by many observations—the direct demonstration of tumor-specific T cells and antibodies in patients; data showing that the extent and quality of immune infiltrates in cancers often correlates with outcome; the increased incidence of certain cancers in immunodeficient people and mice; and most recently and most directly, the dramatic success of immunotherapy in the treatment of several cancers.
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The specific factors that govern the outcome of interactions between tumor cells and the host immune system are numerous and are still being defined. In the face of this complexity, it is helpful to consider a few overarching principles: