Extracellular collagenic type and structural organization changes in prostate cancer and benign prostatic hyperplasia

Gianluigi Taverna1, Fabio Grizzi2, Piergiuseppe Colombo3, Sara Melegari1, Matteo Justich1, Oliviero De Francesco1, Giorgio Bozzini1, Massimo Lazzeri4, Rodolfo Hurle4, Alessio Benetti4, Luisa Pasini4, Silvia Zandegiacomo4, Roberto Peschechera4, Paolo Casale4, Alberto Mandressi1, Giorgio Guazzoni4
  • 1 Humanitas Mater Domini, U.O. Urologia (Castellanza)
  • 2 Humanitas Clinical and Research Center, U.O. Immunologia e Infiammazione (Rozzano)
  • 3 Humanitas Clinical and Research Center, U.O. Anatomia Patologica (Rozzano)
  • 4 Humanitas Clinical and Research Center, U.O. Urologia (Rozzano)

Objective

It is now ascertained that stromal-epithelial interactions play a crucial and poorly understood role in carcinogenesis and prostate cancer progression. Tumor stroma is a complex and dynamic set of cells that includes a fibroblastic component often referred to as cancer-associated fibroblasts and a collagenic and non-collagenic extracellular reactive matrix. In the present study we investigate the collagenic extracellular reactive matrix in a series of prostate cancer biopsy specimens and benign prostatic hyperplasia (BPH) following transurethral resection of the prostate (TURP). Particularly the study focused on the type of collagen composition and its spatial organization.

Materials and Methods

Sixty prostate specimens were investigated. Fifty specimens were diagnosed as prostate carcinoma and 15 as benign prostate hyperplasia. The samples were fixed in 10% formaldehyde and paraffin-embedded. Two-micrometer thick sections were cut and stained with picric acid-sirius red staining to distinguish type I and III collagen using a polarized light microscopy. The ratios of collagen I/III were automatically evaluated using a computer-aided image analysis system. The spatial organization was evaluated on unstained tissue sections by combining a multi-photon microscopy and an open-source MATLAB software framework that includes two separate but linked packages "CurveAlign" and "CT-FIRE". All of the data were analyzed using Statistica software (StatSoft, Inc., Tulsa, OK, USA) and GraphPad Prism 5 (San Diego, California, USA). P-values of ≤ 0.05 were considered to be statistically significant.

Results

By observing the stained sections with Picro-Sirius Red we found different conformations of the collagenic extracellular matrix. Collagen matrix is characterized by a set of highly irregular fragments with different size, size and roughness. In particular, the tumor microenvironment consists of thin collagen fibers while dense plaques have been observed in the microenvironment that characterizes BPH status. Additionally, we found that in BPH type III collagen is less represented if compared to the low and high-grade tumoral tissues. A statistically significant difference was identified between BPH and biopsies of patients with low-grade tumor and in whose fragment no neoplastic cells were observed (p<0.001). In addition, the alignment of collagen fibers is much more pronounced in biopsy of prostate cancer patients than in tissues of patients with BPH.

Discussions

Prostate stroma is a complex dynamical framework, which involves multiple pathways that are dependent on the homeostatic balance between several growth factors. The topographical organization of collagen within the tumor microenvironment has been implicated in modulating cancer cell migration and independently predicts progression to metastasis. It’s known that collagen matrices with small pores and short fibers, triggers a conserved transcriptional response and subsequent motility switch in cancer cells resulting in the formation of multicellular network structure. An initial step in cancer metastasis is the migration of tumor cells through the extracellular matrix and into the lymphatic or vascular systems. Several features of the tumor ECM have been associated with progression to metastasis. In particular, regions of dense collagen are co-localized with aggressive tumor cell phenotypes in numerous solid tumors, including breast, ovarian, pancreatic and brain cancers. However, sparse and aligned collagen fibers at the edges of tumors have also been reported to correlate with aggressive disease. It remains unclear whether and how collagen architectures have a role in driving metastatic migration programs or if they simply correlate with progression of the tumor [1].

Conclusion

Collagen type (type I versus type III) composition and its spatial organization i.e. alignment is different when evaluated in tumoral versus inflammatory state. Given the dynamical process of tissue matrix remodeling, our findings first demonstrated that stromal collagen alignment might provide additional, clinically-relevant information about prostate cancer and underscores the importance of stroma-cancer interactions.

Reference

1. Velez DO, Tsui B, Goshia T, Chute CL, Han A, Carter H, Fraley S.
3D collagen architecture induces a conserved migratory and transcriptional response linked to vasculogenic mimicry. Nat Commun. 2017 Nov 21;8(1):1651.

Argomenti: