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Thomas et al. J Transl Genet Genom 2024;8:249-77 https://dx.doi.org/10.20517/jtgg.2024.15 Page 255

inflammatory and growth signals, basement membrane dysfunction initiating cell-to-matrix and
intercellular interactions regulating cell proliferation, migration, and differentiation of both stromal and
epithelial cells, fibroplasia, angiogenesis, ECM remodeling, and wound contraction [Figure 1]. However, the
persistence of this repair process resulting in a chronic, non-healing wound and fibrosis, can affect any
tissue and organ system in the human body [86-88] .

In 1863, Rudolf Virchow first recognized the association between wound healing phases in tissue and
tumorigenesis. Clinical similarities suggested shared common cellular and molecular signatures between the
two conditions. This insight led Scottish pathologist Dr. Alexander Haddow to deduce cancers as wounds
that overheal [89,90] . However, clinical evidence indicated that in cancer, reactive stroma is not self-limited and
is tumor-promoting, which led Dr. Harold Dvorak to postulate that "tumors are wounds that do not
[86]
heal" . Owing to Paget’s "seed and soil hypothesis", reactive stroma has emerged as essential soil regulating
multiple aspects of tumorigenesis, including initiation, development, progression to metastases, and most
[91]
importantly, development of therapeutic resistance .

Reactive stroma is heterogeneous in its makeup, exhibiting both organ- and tumor-specific characteristics.
The prevalence and abundance of reactive stroma serve as disease-defining factors and are associated with
poor prognosis in several solid tumors, including colon carcinoma, head and neck cancer, HER2-negative
early breast cancer, squamous cell carcinoma, and rectal cancer [20,92-96] . In prostate cancer, reactive stroma co-
evolves with tumor development, and its relative abundance is quantified as reactive stromal grade (RSG).
An RSG of 3 represents when more than 50% of the prostate tumor area is composed of reactive stroma,
and the latter is associated with earlier biochemical recurrence and worse prognosis [97,98] . Reactive stroma in
prostate cancer is composed of CAFs that can transdifferentiate into cancer-associated myofibroblasts
(myCAFs) or inflammatory fibroblasts (iCAFs), with an expanded and modified ECM with collagen
deposition, dense microvessels, and immune infiltrates [Figure 1] [11,17,99] . Tissue recombinant experiments
demonstrated that prostate cancer-derived CAFs promote tumor growth in vivo while normal fibroblasts
inhibit the process, thus confirming the critical nature of reactive stroma in prostate tumor growth and
development [100-102] .

MOLECULAR FEATURES OF REACTIVE STROMA
TGF-β signaling
Cytokines, such as TGF-β, play a crucial role in regulating cell fate and reactive stromal response. TGF-β
induces the differentiation of stromal cells into vimentin and smooth muscle alpha-actin-positive myCAFs,
thereby initiating a wound repair-like reactive stroma. Concurrently, TGF-β also modulates the
composition of the ECM by inducing the expression of collagen 1 and tenascin-C in stromal cells [10,17] .
TGF-β is also critical in modulating the immune reaction. It can suppress interleukin 2 (IL-2) synthesis and
T-cell proliferation, as well as regulate the differentiation of both CD4 T cells and regulatory T cells (Tregs).
+
Cytokines such as IL-10, IL-4, and TGF-β secreted by reactive stromal cells and immune-suppressive cells
like Tregs can increase the polarization of M2 macrophages. M2 macrophages have been shown to enhance
angiogenesis, tissue remodeling, and modulate the immune microenvironment by expressing human
leukocyte antigen (HLA-DR) and programmed death-ligand 1 (PD-L1), resulting in the suppression of the
immune system [103-105] .

Although the expression of TGF-β increases from prostatic intraepithelial neoplasia (PIN) to the
development of prostate cancer lesions [10,17] , the biological activity of TGF-β within TME is not cancer-
specific. TGF-β is a fundamental regulator of different cellular processes in adult differentiated biology .
[106]
Thus, the biological activity of TGF-β activity is essentially indistinguishable whether in a wound repair,