Cancer-associated fibroblasts and their putative role in potentiating the initiation and development of epithelial ovarian cancer

Abstract

The progression of ovarian cancer, from cell transformation through invasion of normal tissue, relies on communication between tumor cells and their adjacent stromal microenvironment. Through a natural selection process, an autocrine-paracrine communication loop establishes reciprocal reinforcement of growth and migration signals. Thus, the cancer-activated stromal response is similar to an off-switch-defective form of the normal, universal response needed to survive insult or injury. It is becoming clearer within the cancer literature base that tumor stroma plays a bimodal role in cancer development: it impedes neoplastic growth in normal tissue while encouraging migration and tumor growth in a co-opted desmoplastic response during tumor progression. In this review, we discuss this reciprocal influence that ovarian cancer epithelial cells may have on ovarian stromal cell-reactive phenotype, stromal cell behavior, disrupted signaling networks, and tumor suppressor status in the stroma, within the context of cancer fibroblast studies from alternate cancer tissue settings. We focus on the exchange of secreted factors, in particular interleukin 1β and SDF-1α, between activated fibroblasts and cancer cells as a key area for future investigation and therapeutic development. A better understanding of the bidirectional reliance of early epithelial cancer cells on activated stromal cells could lead to the identification of novel diagnostic stromal markers and targets for therapy.

Figure 1

Histomorphology and interaction of ovarian cancer epithelial cells and CAFs. The morphologic characteristics of low-grade serous ovarian carcinoma include a papillary growth architecture and uniform nuclei (A and B; hematoxylin and eosin stain), with a comparatively high proportional contribution of cancer stromal cells identified by immunohistochemistry for α-SMA (C and D), a marker that highlights activated reactive CAFs (indicated by black arrows). The altered histomorphology of high-grade serous carcinoma is characterized by a distinctive growth pattern of stratified epithelium with high mitotic rate and a threefold variation in nuclear size and pleomorphism (E and F; hematoxylin and eosin stain). Nuclear atypia are highlighted by red arrows. High-grade serous carcinoma displays a high proportion of CAFs (G and H) highlighted here by immunohistochemistry for α-SMA (black arrows). Scale bars, 50 µm. Magnification, x200 (A, C, E, and G); x400 (B, D, F, and H).

Figure 2

The contribution of CAFs to malignant progression of ovarian cancer. (A) Normal ovarian tissue is composed of ovarian or fallopian tubal epithelial cells and an extracellular microenvironment consisting of quiescent fibroblasts and other supportive mesenchymal cell types that collectively inhibit inappropriate or preneoplastic epithelial proliferation. (B) Transition from normal to preneoplastic, or neoplastic, ovarian or fallopian tubal epithelial cells involves reciprocal secretory communication with activated myofibroblasts, whether tissue resident or recruited from circulation. (C) Progression to malignant ovarian cancer relies, at least initially, on a secretory co-opting of ovarian CAFs through exchange of intercellular secreted factors (e.g., chemokines like IL-1β and GRO-α) with CAFs to facilitate dissemination to theomentum. CAFs may directly facilitate this metastatic movement, although it is likely that EMT of ovarian or fallopian tumor cells provides a reservoir of secretory, ECM-digesting, migratory CAF-like cells.

Figure 3

Model of critical pathways and mechanisms in the activation of ovarian fibroblasts by secretory interaction with neoplastic ovarian cancer cells. (A) Secreted activation signals, such as IL-1β, IL-6, and IL-8 or GRO-α, from neoplastic ovarian or fallopian tubal cancer epithelial cells stimulate a stromal phenotypic shift from quiescent to activated ovarian or omental fibroblasts. Activated CAFs are proliferative, are migratory, and secrete a variety of ECM-restructuring factors (e.g., FAP-1α, urokinase-type plasminogen activator), soluble cancer-activating chemokines (e.g., SDF-1α), and cell surface proteins (e.g., CLIC4). Cancer cell-mediated fibroblast activation selectively promotes tumor angiogenesis, adhesion, migration, and invasion while reducing apoptotic inhibition. (B) Activation of chemokine receptors on ovarian CAFs, including IL-1 receptor 1 (IL-1R1), CD126/CD130, and CXCR2, by ovarian cancer cells likely activates intracellular signaling cascade mediators in ovarian CAFs including IL-1R-associated kinases (IRAK) 1, 2, and 4; tumor necrosis factor α receptor-associated factor 6 (TRAF-6); IL-1-induced activation of c-Jun N-terminal kinase and NF-γB; as well as the c-Jun N-terminal kinase/Janus kinase (JAK)/STAT family members. In ovarian CAFs, these signaling mediators may activate AKT/extracellular signal-regulated kinase 1/2 (ERK1/2)/RBPJγ-mediated transcriptional up-regulation of ovarian CAF-secreted factors that impact epithelial ovarian cancer tumor cell aggressiveness, including the glycoprotein tenascin-C, protease FAP-1α, and myriad interleukins, especially IL-8. In parallel, downstream signals in ovarian CAFs from chemokine-activated receptors facilitate transcriptional or translational inactivation of tumor suppressors, like p53, by yet uncharacterized mechanisms. Once tumor suppressors like p53, PTEN, or Rb are inhibited/inactivated, two intracellular pathways are initiated that are not understood at all: 1) increased cellular production of chemokines, including IL-1β, IL-8, IL-6, and SDF-1α, and 2) chemokine receptors, like IL-1R1, are upregulated. Collectively, ovarian fibroblast activation leads to paracrine ovarian cancer cell stimulation and autocrine stimulation, co-opting a desmoplastic-like stromal response for tumor cell initiation, survival, and inappropriate growth.