Publication: Journal of Pathology – AGE-modified basement membrane cooperates with Endo180 in prostate cancer

Thomas R. Cox, Dec 2014

Endo180 and ECM stiffness cooperate to drive progression in prostate cancer

Our recent collaborative article titled “AGE-modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness and decrease prostate cancer survival” has just been published in The Journal of Pathology.

“How a stiff microenvironment promotes prostate cancer progression”

Prostate cancer acini affected by ECM stiffness

Image: Confocal microscopy of cancer cell acini grown in native or stiff environments

As our body ages, our tissues get stiffer and it is thought that this stiffening is important in the progression of cancer. In this paper we show that as the stiffness of the tissue within the prostate gland increases it is accompanied by an increase in the aggressiveness of prostate cancer which leads to a poor patient survival. This increased stiffness can be as a result of normal age-accumulated changes, so called Advanced Glycation End-products (AGE), or as a result of some metabolic disorders. The consequence is increased aggressiveness of prostate cancer through an Endo180 mechanism working together with these AGEs to promote prostate cancer progression.

Biomechanical strain imposed by age-related thickening of the basal lamina and augmented tissue stiffness in the prostate gland coincides with increased cancer risk. Here we hypothesized that the structural alterations in the basal lamina associated with age can induce mechanotransduction pathways in prostate epithelial cells (PECs) to promote invasiveness and cancer progression. To demonstrate this, we developed a 3D model of PEC acini in which thickening and stiffening of basal lamina matrix was induced by advanced glycation end-product (AGE)-dependent non-enzymatic crosslinking of its major components, collagen IV and laminin. We used this model to demonstrate that antibody targeted blockade of CTLD2, the second of eight C-type lectin-like domains in Endo180 (CD280, CLEC13E, KIAA0709, MRC2, TEM9, uPARAP) that can recognize glycosylated collagens, reversed actinomyosin-based contractility [myosin-light chain-2 (MLC2) phosphorylation], loss of cell polarity, loss of cell–cell junctions, luminal infiltration and basal invasion induced by AGE-modified basal lamina matrix in PEC acini. Our in vitro results were concordant with luminal occlusion of acini in the prostate glands of adult Endo180𝚫Ex2–6/𝚫Ex2–6 mice, with constitutively exposed CTLD2 and decreased survival of men with early (non-invasive) prostate cancer with high epithelial Endo180 expression and levels of AGE. These findings indicate that AGE-dependent modification of the basal lamina induces invasive behaviour in non-transformed PECs via a molecular mechanism linked to cancer progression. This study provides a rationale for targeting CTLD2 in Endo180 in prostate cancer and other pathologies in which increased basal lamina thickness and tissue stiffness are driving factors.

View article on The Journal of Pathology homepage
View abstract on PubMed

Rodriguez‐Teja M, Gronau JH, Breit C,  Zhang Y, Minamidate A, Caley MP, McCarthy A, Cox TR, Erler JT, Gaughan L, Darby S, Robson C, Mauri F, Waxman J, Sturge J. AGE‐modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness and decrease prostate cancer survival
The Journal of Pathology; Mar;235(4):581-92 (2015) | doi: 10.1002/path.4485