In solid cancers, invasion and metastasis account for more than 90% of mortality. However, in the current armory of anticancer therapies, a specific category of anti-invasion and antimetastatic drugs is missing. Here, we coin the term ‘migrastatics’ for drugs interfering with all modes of cancer cell invasion and metastasis, to distinguish this class from conventional cytostatic drugs, which are mainly directed against cell proliferation. We define actin polymerization and contractility as target mechanisms for migrastatics, and review candidate migrastatic drugs. Critical assessment of these antimetastatic agents is warranted, because they may define new options for the treatment of solid cancers.

No abstract

IntroductionDifferentiation of hematopoietic stem cells and progenitors into various lineages is controlled by a complex array of extrinsic and intrinsic factors. [1][2][3][4] Myeloid and erythroid blood cells develop from a common myeloid progenitor, which differentiates into either megakaryocytes and erythrocytes, or granulocytes and macrophages. Several experimental strategies including gene targeting, expression pattern analysis, antisense, and overexpression studies led to the identification of transcription factors that are required for formation, survival, and proliferation of multilineage progenitors and that direct the differentiation and maturation of individual lineages. Specifically, factors like SCL, Rbtn2, GATA-2, and c-Myb were found to be essential for multipotent cells. 5 In more mature cells, the expression of SCL, GATA-1, c-Myb, Rbtn2, FOG, and EKLF is a prerequisite for proper development of the erythroid lineage. On the other hand, factors of the C/EBP family, PU.1, Egr-1, c-Myb, and AML-1 play an important role in the myeloid lineage. [6][7][8][9] It has been suggested that in the common myeloid progenitor the concentrations of intracellular lineage-determining regulators are to be low and balanced. 10,11 During the commitment process this balance is disturbed either in a stochastic or instructed manner, resulting in the prevalence of a particular set of factors and the subsequent development of the respective lineage. Several factors were identified that instruct progenitor cells to develop along a specific lineage. Using the model of primary chicken myb-etstransformed multipotent progenitors (MEP), 12 it was demonstrated that PU.1 and C/EBP␤ forced differentiation of MEP progenitors into myeloid cells, and C/EBP␣ only into eosinophils. 13,14 In mammalian cells, Egr-1 was found to commit myeloid cells into the macrophage lineage with the concomitant block to differentiation into granulocytes. 15 The c-myb proto-oncogene is essential for early definitive myeloid and erythroid cells as documented by gene targeting experiments. 16 It is required for the expansion of immature cells of the myeloid, erythroid, and lymphoid lineages and is downregulated during their terminal differentiations. 17 The v-myb gene transduced by avian myeloblastosis virus (AMV), as well as its truncated homologue, transduced as the myb-ets fusion by E26 leukemia virus, are oncogenes that specifically affect the developmental programs of avian hematopoietic cells. AMV v-Myb interferes exclusively with the development of the macrophage lineage of both primitive and definitive hematopoietic cells by blocking terminal differentiation of macrophage precursors and activating their self-renewal capacities in vitro. It causes fatal acute monoblastic leukemia in chicks. E26 v-Myb-Ets fusion protein transforms multipotent progenitors of primitive hematopoietic cells (blastoderm), and committed erythroid and myeloid cells of bone marrow. It induces erythroid leukemia in infected chicks. [18][19][20][21][22] Thus, the E26 v-Myb-E...

Metastatic spreading of cancer cells is a highly complex process directed primarily by the interplay between tumor microenvironment, cell surface receptors, and actin cytoskeleton dynamics. To advance our understanding of metastatic cancer dissemination, we have developed a model system that is based on two v-src transformed chicken sarcoma cell lines-the highly metastatic parental PR9692 and a non-metastasizing but fully tumorigenic clonal derivative PR9692-E9. Oligonucleotide microarray analysis of both cell lines revealed that the gene encoding the transcription factor EGR1 was downregulated in the non-metastatic PR9692-E9 cells. Further investigation demonstrated that the introduction of exogenous EGR1 into PR9692-E9 cells restored their metastatic potential to a level indistinguishable from parental PR9692 cells. Microarray analysis of EGR1 reconstituted cells revealed the activation of genes that are crucial for actin cytoskeleton contractility (MYL9), filopodia formation (MYO10), the production of specific extracellular matrix components (HAS2, COL6A1-3) and other essential pro-metastatic abilities.