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Maitland Prostate cancer: from bench to bedside

also have the capacity to spread at an early stage LNCaP cells have been in culture for more than
of the cancer; and (3) castration resistant disease 40 years with a hypotetraploid karyotype (84-87
(after hormone treatment) which has been shown chromosomes) and are genetically unstable. Both
in gene expression and mutational studies [9-11] to cell growth and secreted proteins (such as PSA) are
represent a completely different type of cancer. sensitive in a biphasic manner to androgens, but also
Although castration-resistant prostate cancer shares to estrogens, as the androgen receptor gene carries a
some trunk or driver mutations [12] , it has developed mutation (T877A - selected/induced by the estrogenic/
a completely new mutation sub-set and ultimately mutagenic treatment of the patient?) which broadens
the fatal lesion in prostate cancer, which often has the hormone binding capacity of the AR protein.
a partly or wholly neuroendocrine phenotype and is
impervious to most chemotherapy treatments [13,14] . To overcome the latter property and to render LNCaP
To simply pick a cell line to represent “prostate more sensitive to antiandrogen drugs, derivatives have
cancer” is not sufficient, as is becoming increasingly been generated by transfection of extra copies of the
apparent with our depth of analysis. If we now look AR gene (LNCaP-AR). AR low/negative (C4-2) and
back through the online scientific literature, which neuroendocrine derivatives can be readily generated
contains more than half a million references to LNCaP by growth in selective media, specific gene knockout,
cells together with “prostate cancer treatment” in key and application of epigenetic modifiers such as
words, one must begin to doubt the validity of many histone deacetylase inhibitors.
of these previous experiments.
It is therefore no surprise that the LNCaP genome
There is also the question of timeliness. The castration is packed with secondary mutations, but also that
resistant cancer of the 1980s was very different LNCaP itself has a propensity to grow in estrogen
from that developed after the current generation of supplemented medium. This is partly due to the
androgen therapies. For example, LNCaP was derived original culture/xenografting procedure which is
from a patient who had failed on the combination drug described in the original paper from 1980 [15] , often
treatment of Estramustine (estrogen and nitrogen forgotten by current day researchers, who simply
mustard, both hormone suppressive and strongly treat it as an androgen responsive cell line.
mutagenic) [15] .
THE FUTURE: TEAM INTEGRATION AND
Origins of the LNCaP cell line STRATIFIED MEDICINE
The LNCaP cell line was derived (1977) from a
50-year-old Caucasian male patient with stage D The steep and downhill learning curves:
prostate cancer, and strong evidence of extraprostatic beware of the next bandwagon
disease as determined by high serum levels of prostatic When developing new anti-androgen receptor
acid phosphatase ( > 20 times normal). The patient drugs, LNCaP has been the preclinical and basic
had been treated with oral estrogens, orchiectomy and science tool of choice. Given its responsiveness to
an aggressive course of estramustine chemotherapy. estrogens and the presence of a mutant androgen
He also presented with metastases to the bone. At this receptor, this is perhaps surprising. To develop the
point a biopsy from the supraclavicular lymph node new generation of androgen receptor inhibitors such
was taken and cultured in RPMI medium containing as Enzalutamide, a variant of LNCaP into which
15% fetal calf serum and antibiotics. The cells grew extra copies of the androgen receptor gene (in
rather slowly, although a single clone emerged with an un-mutated wild type form) had been inserted,
a population doubling time of 24 h, known as the fast was used [16] . The consequences of extra androgen
growing clone which is now supplied by the ATCC for receptor expression within the cells appeared to
research purposes. make them especially sensitive to the anti-androgen
drugs such as Enzalutamide. Does this represent a
The cells grow well (from a 107 cell inoculum) true reflection of the drug efficacy? It is somehow
in immunocompromised mice to form poorly redesigning the test system to fit the drug. Whilst
differentiated adenocarcinomas, and whilst tumor there is no doubt that Enzalutamide is a powerful and
take is better in male compared to female mice, the virtually irreversible inhibitor of androgen receptor in
rate of tumor growth is independent of the sex of the the clinic [17-21] , perhaps there are more complexities in
recipient mouse. No distal metastases are found with real cancer tissues than seen in this now, increasingly
the parental line unless co-inoculated with fibroblast artificial experimental cancer model. In our own
cells, although highly malignant sublines have experiments, LNCaP has proven to be hypersensitive
subsequently been derived. to treatment by Docetaxel compared to every primary
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ November 17, 2017 263