Tumor-stroma co-evolution in prostate cancer progression and metastasis.
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.
Josson
Sajni
S
Uro-Oncology Research, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Matsuoka
Yasuhiro
Y
Chung
Leland W K
LW
Zhau
Haiyen E
HE
Wang
Ruoxiang
R
D001859:Bone Neoplasms / Q000556:secondary; D018450:Disease Progression; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin / Q000378:metabolism; D018384:Oxidative Stress; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D053245:RANK Ligand / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
D053244:Osteoprotegerin; D053245:RANK Ligand