The Microenvironment Determines The Fate Of Transformed Cells

The multicellular composition of the organism necessitates coordination among cells of varied specializations through intercellular communication. Growth factor, hormone, and Integrin signaling pathways all contribute to maintaining tissue architecture. The extracellular matrix is a network of macromolecules that provides contextual information and an architectural scaffold for cell adhesion and migration. The condition of the stroma is an important factor to determine the susceptibility of cells to transformation. The loss of spatial control leads to the disorganization of normal tissue architecture that is the hallmark of neoplastic transformation.

Mechanical forces on cell shape, generated by insoluble extracellular matrix molecules, contribute, and may be rate limiting to the progression through G1 [Huang and Ingber 1999]. Several important cell cycle events are dependent on cell-substratum adhesion in nontransformed cells, including the activation of G1 CDKs and the expression of Cyclin A. Integrin occupation and clustering leads to stimulation of multiple early mitogenic events associated with the transition from G0 to G1 in the cell cycle, including EGR genes. Unanchored fibroblasts remain arrested in mid-Gj and display a marked reduction of Cyclin E/CDK2 kinase activity and increased levels of the CDK Inhibitors, P27KIP1 and P21CIP1/WAF1 [Fang et al. 1996; Huang and Ingber 1999]. The adhesion requirement of these events is abrogated in cells transformed by ras, which may be due to the downregulation of P27KIP1.

Breast cancer cells can colonize bone because they activate genetic programs that mediate cell-cell communication with osteoblasts and osteoclasts. Plasticity of the bone structure is maintained by a balance between osteoblastic and osteoclastic activities. This balance is regulated by various signals between the two cell types. Important interactions in the regulation of bone resorption include the induction and activation of osteoclastogenesis, induced by binding of RANK Ligand on osteoblasts to RANK on osteo-clast progenitors, and the suppression of osteoclasto-genesis, mediated by binding of RANKL to soluble Osteoprotegerin, which interferes with the engagement of RANK. Osteoprotegerin is a member of the TNFR family and a negative regulator of osteoclast function. Bone metastases of breast cancer typically express RANKL and thus activate bone resorption.

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