New study below [1].
Not so long ago, PCa that was refractory (i.e. resistant) to ADT was described as being hormone independent.
The three dominant cell lines in PCa research have been LNCaP (from lymph node), DU145 (from brain) & PC-3 (from bone). PC-3 "cells do not respond to androgens" & "do not express PSA" [2].
"It is well established that human PCa bone metastasis form osteoblastic lesions rather than osteolytic lesions seen in other cancers like breast cancer. Similarly, PC-3 and DU145 cells form osteolytic tumors." [3]
It came as a surprise that in real-life ADT-resistant PCa, the androgen receptor [AR] continues to be involved in proliferation. The term castrate-resistant was coined [CRPC], & researchers went on to develop Zytiga & Xtandi, which essentially target AR. i.e. simply a continuation of the Huggins strategy.
PCa cells develop various tricks to survive in a low-androgen environment - including steroidogenesis, the generation of steroid hormones from cholesterol.
What seems to have been missed is consideration of a basic control mechanism in autocrine signaling.
Example. It has been understood for quite a while that in normal prostate cells, there is an enzyme that acts on calcidiol (inactive vitamin D) to form calcitriol (hormonal vitamin D), & that the presence of calcitriol will stimulate the expression of a second enzyme to metabolize & clear calcitriol. This is how cells create a window for a hormone to do its thing, & prevent continuous stimulation. In PCa, the expression of the first enzyme is down-regulated, while the second enzyme is up-regulated. Less calcitriol is created & it is cleared faster.
The "novel" mechanism [4] of the new study isn't so new. It's the same old story. The cancer suppresses the enzyme associated with androgen clearance.
"Androgen receptor signaling is critical for prostate adenocarcinoma, even after androgen deprivation therapy. Persistence of intratumoral androgens has been found in castration-resistant prostate cancer and attributed to increased in situ synthesis. Recently, Sharifi and colleagues reported an additional mechanism that can enhance local androgenic exposure: downregulation of an androgen-inactivating enzyme." [4]
From the Discussion section of [1]:
"In summary, our data bring clarity to what has generally been a perplexing link between HSD17B4 and the development of CRPC. When viewed through the lens of the enzymatic properties of a single specific isoform encoded by HSD17B4 variant 2, which is responsible for androgen inactivation, the functional expression of this variant transcript, its loss in the clinical development of CRPC, and its effects on in vivo CRPC growth, all concordantly point toward a causal role in the development of the lethal form of PCa."
-Patrick
[1] ncbi.nlm.nih.gov/pmc/articl...
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