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Page 254 Thomas et al. J Transl Genet Genom 2024;8:249-77 https://dx.doi.org/10.20517/jtgg.2024.15

Multiplex profiling has revealed a significant enrichment of T and B lymphocytes in the mouse prostate
gland due to aging. Specifically, a strong correlation was observed between age and enrichment of
+
+
+
programmed cell death protein 1 positive (PD-1 ) CD4 and CD8 T cells in the mouse prostate gland.
PD-1, a cell membrane protein, plays a critical role in inhibiting both T and B-cell immune response, and is
a marker for T-cell "exhaustion" [47,53,72] . Intriguingly, estrogen modulates immune cells of both myeloid and
lymphoid lineages in a tissue-context-dependent manner . Given the presence of both myeloid and
[73]
lymphoid cells in prostate gland homeostasis [47,48] , understanding the dynamic changes in the immune
profile within the prostate gland in the context of testosterone deficiency and estrogenic dominance is
crucial for comprehending disease development in an aging prostate.

TUMOR-STROMA INTERACTIONS
While tissue-emergent/reactive stromal responses in carcinomas are often considered secondary to
epithelial changes, the limited progression of many epithelial tumors from in situ lesions despite harboring
genetic abnormalities associated with malignancy raises questions about the driving molecular factors of
neoplasms [74,75] . Recombinant studies in murine models have provided evidence suggesting that the stromal
microenvironment is a key determinant in promoting prostate carcinogenesis [76-80] . Moreover, exogenous
insults directly affecting the stroma have been identified as critical initiators of the carcinogenic process in
various other solid tumors. For instance, ultraviolet radiation-induced dermal atrophy has been shown to
precede keratinocyte tumors, while chemicals in cigarette smoke metabolically promote cancer by inducing
autophagy and premature aging in the host stromal microenvironment in an organ such as the breast [75,81,82] .
In another example, obesity-induced metabolites derived from gut microbiota induce senescence in hepatic
stellate cells, which then secrete inflammatory and tumor-promoting factors that facilitate the development
of hepatocellular carcinoma in mice exposed to chemical carcinogens . Collectively, these instances
[83]
suggest that the tissue stroma may indeed play a primary role in initiating and promoting cancer
development.

Thus, the experimental evidence cited above suggests that aging or insult-driven changes of the stroma
create a permissible emergent/reactive tissue or organ environment (soil) that promotes the growth of
monoclonal or polyclonal tumors (field cancerization). However, based on this view, sustainable treatment
or cure for cancer will be difficult to attain as long as the reactive soil persists . Therefore, there is a
[75]
pressing need to characterize the stromal compartment of solid tumors. One of the main limitations in
characterizing reactive stroma in prostate cancer is the heterogeneity of cancer-associated fibroblasts
(CAFs) that make up the TME. Stromal heterogeneity is partially explained by the fact that CAFs can be
derived from the activation of tissue-resident fibroblasts, mesenchymal stem cells, vimentin-positive
periacinar cells, circulating bone marrow-derived precursors, vessel-associated pericytes, and endothelial
cells [10,11] . Spatial transcriptomic analysis of radical prostatectomy-derived tissue, in addition to stromal cell
lineages identified from single-cell sequencing analyses of mouse prostate stroma, suggests the presence of
reactive stromal cells with different transcriptional programs and functions within the prostate cancer
TME [84,85] . Additionally, the phenotypic plasticity of the activated stromal cells further underscores the
[11]
dynamic nature of the reactive stroma . Hence, characterizing a moving target such as TME to understand
tumorigenesis, development, and progression becomes a challenging endeavor.

STROMAL RESPONSE IN PROSTATE CANCER
The coordinated host emergent response to tissue injury involves the collective action of cells that make up
the connective tissue/stroma and the extracellular matrix (ECM) products. The normal reactive stromal
response to injury is self-limited and regulated spatially and temporally to re-establish tissue integrity and
reset homeostasis. The mechanisms underlying reactive/emergent stromal response include the release of