Tumor-stroma co-evolution in prostate cancer progression and metastasis

Abstract

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.

Figure 1

Tumor stroma interactions in the prostate microenvironment. A. Normal prostate microenvironment contains luminal cells, basal cells, neuroendocrine cells, stem cells and the stroma component contains fibroblast and neurons. B. Prostate cancer initiation occurs with increased reactive oxygen species generation and increased mutation in cancer cells. The mutations observed are non-clonal p53 and androgen receptor mutations and alterations in the redox environment such as decreased glutathione transferase (GSTP1) and manganese superoxide dismutase (MnSOD) function and increased NADPH oxidase 1. C. As the cancer advances it interacts with the microenvironment and these interactions enter a vicious cycle promoting cancer aggressiveness. As tumors grow large, they develop hypoxia and limited nutrients, conditions which can induce EMT and increase mobility. Additionally the cancer gains the characteristic of mimicry even before the cancer cells metastasize to the bone. Some of the genes involved in osteomimicry are β2-microglobulin, PTHrP, RANKL and other bone proteins secreted by the cancer cell, such as, osteocalcin, osteopontin, bone sialoprotein and osteonectin. Additionally cancer associated fibroblasts also undergo alterations, such as increases in, brain derived neurotrophic factor (BDNF), CCL5, CXCL5, CXCL12, versican and tenascin.

Figure 2

Cancer-stromal interaction in the bone microenvironment. Cancer cells gain access to bone through the bone endothelium which expresses specific adhesion molecules such as P-selectin, E-selectin, ICAM-1 and VCAM-1, which interact with cancer cells. Cancer cells modulate cancer-associated fibroblasts in the bone microenvironment. Cancer cells release bone specific proteins and other proteins which induce bone turnover, these include β2microgloblulin, BMPs, endothelin, IGF, IL-1, IL-6, OPG, PTHrP, TGFβ, urokinase and VEGF.