Page 79 - Read Online

Page 256 Thomas et al. J Transl Genet Genom 2024;8:249-77 https://dx.doi.org/10.20517/jtgg.2024.15

tissue fibrosis, or TME. TGF-β, secreted by both epithelial cells and fibroblasts, is critical for coordinating
tissue repair and homeostasis through its context-dependent pleiotropic functions. For example, TGF-β
induces cytostasis in non-transformed epithelial cells, while in endothelial and mesenchymal cells, it
stimulates proliferation. Additionally, TFG-β can both induce and suppress apoptosis, suggesting that other
critical signaling inputs mediate TGF-β-induced cellular survival and cell death . Epithelial-to-
[107]
mesenchymal transition (EMT) is an important cellular event common in wound repair, fibrosis, and
cancer. TGF-β-induced signaling, either independently or in coordination with critical mediators of tissue
homeostasis such as Wnt and NOTCH, induces EMT by repressing inter-epithelial adhesion and junctional
complexes while upregulating mesenchymal markers including ECM remodeling enzymes like matrix
[108]
metalloproteinases (MMPs), facilitating cell migration . Apart from TGF-β, growth factors such as FGFs
and PDGF, which are critical for wound healing and tissue remodeling, also regulate reactive stromal
biology in prostate cancer [109,110] .

Remodeled ECM
ECM remodeling serves as another critical regulator of tissue biology, integrity, and, most importantly,
maintaining homeostasis. Beyond providing physical support, the ECM plays a pivotal role in cell adhesion,
migration, initiating angiogenesis, tissue development, and repair . The cells of the reactive stroma
[111]
actively overexpress ECM proteins (collagens, elastin, fibronectin, tenascin-C, and hyaluronic acid), MMPs,
fibroblast activation protein (FAP), and lysyl oxidases [17,111-113] . MMPs, in particular, play a critical role in
remodeling the ECM and inducing modifications that influence its topographical and mechanical
properties. In healthy tissue, ECM remodeling is a tightly regulated process that involves the counterbalance
[114]
of ECM synthesis with the activity of MMPs, MMP inhibitors, and lysyl oxidases .

Damage to the ECM due to tissue injury initiates an emergent response referred to as a "wound healing
cascade" to repair damaged tissue and reset tissue homeostasis . In cancer, ECM is damaged and exposure
[111]
to chronic remodel signals generated from both the cancer cells and reactive stromal cells results in a
chronic wound-healing cascade. Consequently, the dysregulated ECM remodeling and turnover results in
the development of fibrotic tissue (desmoplasia) with enhanced stiffening around the tumors. This ECM
alteration affects every aspect of tumor biology, including the regulation of proliferation, differentiation,
gene expression, cell adhesion, migration, invasion, etc. . Beyond its regulatory control, ECM also
[111]
influences immunogenicity, oxygenation, and the response of cancer to treatments. Thus, a reactive stroma
composed of extensively remodeled ECM is correlated with poor prognosis in cancer [111,115] .

Activated angiogenic niche
Cells within the vasculature network, primarily endothelial cells (EC), pericytes, and vascular smooth
muscle cells, constitute additional critical components of the tissue stroma and are essential regulators of
prostate homeostasis . In healthy tissue, the non-angiogenic EC interacts with a complex basement
[10]
membrane composed of collagen IV, laminin, perlecan (heparan sulfate proteoglycan), and entactin/
nidogen via integrin . However, in response to wounding and cancer, the reactive stromal cells
[116]
(myofibroblasts or CAFs) secrete ECM such as collagen I and IV, fibronectin, secreted protein acidic and
rich in cysteine (SPARC), tenascin, heparan sulfate proteoglycans, connective tissue growth factor, and
VEGF. On interaction with these reactive stromal products, the quiescent EC transitions into an activated
status/angiogenic switch, resulting in the formation of phenotypically distinct blood vessels with aberrant
branching and enhanced leakiness [10,116] . Hypoxia is another critical feature common to both tissue injury
and TME. Hypoxia-induced activation of hypoxia-inducible factors (HIFs) in both epithelial and stromal
cells results in the secretion of proangiogenic factors that modulate vessel maturation. Thus, the new growth
of vascular network in response to reactive stromal response in the TME is critical in regulating the
proliferation, growth, and progression of solid tumors [117-119] .