Cancer development is complex and involves several layers of interactions and pleotropic
signaling mechanisms leading to progression. Cancer cells associate with resident
stromal fibroblasts, smooth muscle cells, macrophages, endothelium, neurons and migrating
cells at metastatic sites and phenotypically and genotypically activate them. These
become an integral part of the cancer cell community through activated cell signaling
mechanisms. During this process, the cancer cells and cells in the cancer microenvironment
"co-evolve" in part due to oxidative stress, and acquire the ability to mimic other
cell types (which can be termed osteomimicry, vasculomimicry, neuromimicry and stem
cell mimicry), and undergo transition from epithelium to mesenchyme with definitive
morphologic and behavioral modifications. In our laboratory, we demonstrated that
prostate cancer cells co-evolve in their genotypic and phenotypic characters with
stroma and acquire osteomimetic properties allowing them to proliferate and survive
in the skeleton as bone metastasis. Several signaling interactions in the bone microenvironment,
mediated by reactive oxygen species, soluble and membrane bound factors, such as superoxide,
beta2-microglobulin and RANKL have been described. Targeting the signaling pathways
in the cancer-associated stromal microenvironment in combination with known conventional
therapeutic modalities could have a synergistic effect on cancer treatment. Since
cancer cells are constantly interacting and acquiring adaptive and survival changes
primarily directed by their microenvironment, it is imperative to delineate these
interactions and co-target both cancer and stroma to improve the treatment and overall
survival of cancer patients.
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