Structure and Function of a Prostate Cancer Dissemination–Permissive Extracellular Matrix

Abstract

Purpose The poor prognosis of metastatic prostate cancer continues to present a major challenge in prostate cancer treatment. The tumor extracellular matrix (ECM) plays an important role in facilitating metastasis. Here we investigated the structure and function of an ECM that facilitates prostate cancer metastasis by comparing orthotopic tumors that frequently metastasize, to poorly metastatic subcutaneous tumors. Experimental Design Both tumors were derived from a human prostate cancer PC3 cell line engineered to fluoresce under hypoxia. Second harmonic generation (SHG) microscopy was used to characterize collagen 1 (Col1) fiber patterns in the xenografts as well as in human samples. Magnetic resonance imaging (MRI) was used to determine albumin-Gd-diethylenetriaminepentaacetate (alb-GdDTPA) transport through the ECM using a saturation recovery MR method combined with fast T1 SNAPSHOT-FLASH imaging. Cancer associated fibroblasts (CAFs) were also quantified in these tumors. Results Significant structural and functional differences were identified in the prometastatic orthotopic tumor ECM compared to the less metastatic subcutaneous tumor ECM. The significantly higher number of CAFs in orthotopic tumors may explain the higher Col1 fiber volumes in these tumors. In vivo, alb-GdDTPA pooling was significantly elevated in metastatic orthotopic tumors, consistent with the increased Col1 fibers. Conclusions Developing noninvasive MRI indices of macromolecular transport, together with characterization of Col1 fiber patterns and CAFs can assist in stratifying prostate cancers for aggressive treatments or active surveillance. These results highlight the role of CAFs in supporting or creating aggressive cancers, and the importance of depleting CAFs to prevent metastatic dissemination in prostate cancer.

A comparison of prostate cancer cell transcriptomes in 2D monoculture vs 3D xenografts identify consistent gene expression alterations associated with tumor microenvironments

“…For example, androgen response plays a significant role in PC and the pathway upregulation observed in 3D models suggests a conducive environment for increased androgen response, which should be accounted for in experimental studies. Further, in xenograft model systems, significant differences in the ECM and tumor microenvironments at different implant sites have been observed, with collagen‐related proteins implicated in facilitating tumor formation 16,17 . This correlates with the upregulation of collagen‐related pathways and the ECM in our 3D data and gives important biological insight into the interplay between tumor cells and surrounding microenvironments.…”

“…The interactions between carcinoma cells and the tumor stroma have been the focus of increasing attention and recognized as important factors in tumor progression and resistance to therapy 14,15 . PC is no exception in this regard and several components of the prostate stroma are known to play significant roles in tumor progression and metastasis 16 . Importantly, factors derived from the PC stroma, such as the DNA damage secretory program, can mediate tumor‐protective effects that promote resistance to chemotherapeutic agents 8 …”

“…14,15 PC is no exception in this regard and several components of the prostate stroma are known to play significant roles in tumor progression and metastasis. 16 Importantly, factors derived from the PC stroma, such as the DNA damage secretory program, can mediate tumorprotective effects that promote resistance to chemotherapeutic agents. 8 The LNCaP, VCaP, and 22Rv1 PC cell lines are widely used for research purposes, both as in vitro 2D monolayers and as 3D xenografts in immunocompromised mice.…”

Nintedanib treatment delays prostate dorsolateral lobe cancer progression in the TRAMP model: contribution to the epithelial‐stromal interaction balance

“…Also, changes in the different ECM compounds could disturb the cross-talk between cells and ECM, leading to disease progression (Theocharis et al, 2016). In addition, not only could ECM remodeling be seen as physiological conditions but also as being part of the disease modulation (Penet et al, 2017). Finally, ECM damages could disturb stromal cell behavior, favor angiogenesis, and the inflammation process associated with the tumor, creating a tumorigenic microenvironment (Lu et al, 2012).…”

Cytoskeleton and ECM tumor mutant peptides: Increased protease sensitivities and potential consequences for the HLA class I mutant epitope reservoir

“…[8][9][10] Considering the possibility of physical barriers, or the degradation of physical barriers in relation to metastasis further suggests considering the possibility that abnormal, [11][12][13][14] or abnormally expressed 15,16 cell shape and ECM proteins could facilitate metastasis. [17][18][19] As it turns out, proteins that participate in the formation of the cytoskeleton and extracellular matrix (CECMPs) represent very large coding regions and thereby are frequently mutated in tumorigenesis, 20,21 that is, the random nature of mutagenesis makes it inevitable that many of these coding regions will be mutated. In some cases, particularly in melanoma, these coding regions have been shown to be candidate drivers.…”