The Stromal–Cancer Cell Connection
Wang et al., pp. 599–610
Prostate cancer often lingers at a relatively benign stage for many years, only to suddenly erupt into evasive, deadly disease that spreads throughout the body. During the disease's progression, stromal cells, which form the supportive network of the prostate gland and engage in constant crosstalk with neighboring cells, start releasing high levels of growth factors, which work together to promote tumor growth. To do so, they require stimuli from epithelial cancer cells but the precise mechanism is poorly understood.
Recently, the authors and others found that prostate-specific tissue kallikrein 4 (KLK4) is a potential activator of protease-activated receptors (PARs) 1 and 2, which are G-protein-coupled receptors implicated in various cancers. Since PAR-1 is characteristically localized in peritumoral stromal cells, Wang et al. explored the possibility that epithelial cancer cells can stimulate stromal cells through PAR-1 activation to result in the release of growth factors and cytokines that drive cancer growth.
Their experiments uncovered a novel double-paracrine feedback loop initiated by KLK4, which is produced exclusively by prostate epithelium. KLK4 activates PAR-1 on prostate stromal cells, which in turn induces stromal cells to release numerous cytokines, including IL-6. Upon binding to its receptors on cancer cells, IL-6 signaling activates androgen-regulated genes such as PSA and KLK4 via STAT3 or MAPK pathways, closing the loop. Uncovering the various communication channels between prostate tumor cells and their microenvironment may lead to novel therapeutic approaches based on interrupting tumor-stroma interactions.
Signal Deprivation in Prostate Cancer
Sun et al., pp. 764–774
Desiniotis et al., pp. 775-789
The growth of prostate cancer is fueled by the androgen receptor (AR), a transcription factor that binds steroid hormones, coactivators and coreceptors of AR, and then translocates to the cell nucleus where the AR-complex activates a number of androgen-responsive genes. Consequently, for the last 70 years the treatment of choice for advanced metastatic prostate cancer has been androgen deprivation therapy. But inevitably, in patients treated with hormonal therapy the tumor becomes androgen-independent; yet these tumors retain their dependence on AR signaling even after they become androgen-independent. Two reports in this issue focus on strategies aimed at intercepting AR signaling by removing the receptor itself from the cells.
Sun et al. generated an adeno-associated virus (AAV) vector to express a short hair-pin-structured RNA directed against the AR gene (ARHP8), which induces apoptotic cell death in AR-positive prostate cancer cells in vitro as they had previously shown. When delivered via tail vein injection into prostate cancer xenograft-carrying mice, ARHP8 dramatically reduced AR gene expression, induced apoptotic cell death and eliminated xenograft tumors within 10 days.
The authors of the second study, Desiniotis et al., went a step further and simultaneously inhibited AR and cAMP-dependent protein kinase A (PKA) with small interference RNAs. Overexpression of PKA's regulatory subunit PKA RIα has been strongly associated with tumor progression and poor prognosis and can activate AR via crosstalk in a ligand-independent manner. Inhibition of both AR and PKA RIα expression with antisense molecules significantly enhanced the anti-proliferative and proapoptotic effects of AR knockdown in androgen-sensitive and in AR ablation-resistant prostate cancer cells.
Taken together, these results demonstrate that novel therapeutic strategies targeting AR signaling offer promising potential for the treatment of hormone refractory prostate cancer.
Quantifying the Risks Associated with Obesity
Renehan et al., pp. 692–702
“… with more than half of all adult Europeans overweight or obese the absolute number of cancer cases that can be blamed on excess body weight could be substantial.”
It's been well known that extra body fat increases the risk of developing cancer. Although the risk per 5 kilogram-per-meter-squared increase in body mass index (BMI) is modest, with more than half of all adult Europeans overweight or obese, the absolute number of cancer cases that can be blamed on excess body weight could be substantial. And the numbers are only expected to increase as people continue to eat more and exercise less.
To establish a baseline for modeling future trends and interventions, Renehan et al. estimated how much of the cancer burden can be attributed to excess body mass index (BMI) in 30 European countries, drawing upon a previously published meta-analysis. Their study revealed that 2.5% of all new cancer cases in men and 4.1% of all new cancer diagnoses in women were directly related to being overweight (BMI ≥ 25). These collectively corresponded to 70,288 new cases, with endometrial, postmenopausal breast and colorectal cancers accounting for 65% of the total.
These results have important implications for setting future research priorities and national health policy as obesity-related cancer affects more women than men and, on a country level, is a greater problem in Central European Countries such as the Czech Republic than for Scandinavian countries such as Denmark.