Axis of evil: molecular mechanisms of cancer metastasis

Abstract

Although the genetic basis of tumorigenesis may vary greatly between different cancer types, the cellular and molecular steps required for metastasis are similar for all cancer cells. Not surprisingly, the molecular mechanisms that propel invasive growth and metastasis are also found in embryonic development, and to a less perpetual extent, in adult tissue repair processes. It is increasingly apparent that the stromal microenvironment, in which neoplastic cells develop, profoundly influences many steps of cancer progression, including the ability of tumor cells to metastasize. In carcinomas, the influences of the microenvironment are mediated, in large part, by bidirectional interactions (adhesion, survival, proteolysis, migration, immune escape mechanisms lymph-/angiogenesis, and homing on target organs) between epithelial tumor cells and neighboring stromal cells, such as fibroblasts as well as endothelial and immune cells. In this review, we summarize recent advances in understanding the molecular mechanisms that govern this frequently lethal metastatic progression along an axis from primary tumor to regional lymph nodes to distant organ sites. Affected proteins include growth factor signaling molecules, chemokines, cell-cell adhesion molecules (cadherins, integrins) as well as extracellular proteases (matrix metalloproteinases). We then discuss promising new therapeutic approaches targeting the microenvironment. We note, however, that there is still too little knowledge of how the many events are coordinated and integrated by the cancer cell, with conspiratorial help by the stromal component of the host. Before drug development can proceed with a legitimate chance of success, significant gaps in basic knowledge need to be filled.

Integrins as a distinct subtype of dependence receptors

“…Many tumors recruit stromal fibroblasts, which both secrete ECM components and apply mechanical tension to the secreted ECM. 17,110 Some tumors that express an integrin inappropriate to their local ECM simply secrete a required ECM component that permits ligation of the integrin. 111,112 In others, tumors may activate cytosolic signaling pathways downstream of integrins that regulate apoptosis.…”

HTPAP gene on chromosome 8p is a candidate metastasis suppressor for human hepatocellular carcinoma

“…Many metastatic suppressors, such as KAI1, CD44, mitogen-activated protein kinase (MAPK) 4, nm23-H1, nm23-H2, KiSS1, and BrMS1, have also been shown no significant effect on the primary tumor growth (Bogenrieder and Herlyn, 2003;Kauffman et al, 2003). Among these, MAPK4 and KiSS1 probably suppress metastasis by inhibiting cancer cell growth at secondary sites.…”

CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells

“…These include adhesion proteins such as integrins as well as enzymes like the metalloproteinases (MMPs), which support tumor invasion in connective tissue. 4,5 Emerging evidence suggests that a third family, the chemokines and their receptors, are involved in organ-specific metastasis. Chemokines are a superfamily of small, secreted proteins (8 -10 kDa) that function to set up immune and inflammatory reactions.…”