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Maitland Prostate cancer: from bench to bedside

Figure 1: Response of primary patient cultures and the LNCaP cell line to docetaxel treatment. Cells were plated at 5,000 cells per
well of 96-well plates, treated with several doses of docetaxel and measured using alamar blue assay at 24 h post-treatment. Primary
prostate epithelial cells cultured from patient samples from different disease grades and LNCaP cells were used (Data from Dr. Fiona
Frame, University of York)

prostate culture, which we have treated with the established cultures are sometimes representative
same concentration of drug [Figure 1]. Unsurprisingly only of the cells that will grow in the laboratory, which
this is also true for a number of signaling pathway may not be the cells that grow quickly in the patient.
inhibitors, such as inhibition of Akt and PI3 Kinase.
LNCaP is null for the PTEN gene, which renders Overcoming clonal bias
the signaling pathways considerably more active. In Clearly the best method is to develop a closer liaison
most prostate cancer patients the situation is less between clinicians working with patient samples
clear cut with only very advanced prostate cancers and the scientists themselves. There are however
having lost both copies of the PTEN gene. Most a number of scientific arguments against this.
earlier stage cancers contain a single copy or express Working with primary samples is time consuming and
the PTEN protein at lower but still biologically active perceived to be prone to failure. To achieve statistical
levels, a phenomenon known as haplo-insufficiency. significance, ironing out the natural patient to patient
In this case our experiments indicated that LNCaP variation in clinical samples, requires multiple
has inactivated a number of emergency or salvage samples far beyond the normal “journal requirements”
pathways during the 40 years in which LNCaP has (currently for at least 2 independent prostate cancer
been cultured on a nutrient rich medium of initially cell lines). How then should those representative
15% and more recently 10% fetal calf serum. These cell lines be chosen? Are they selected because the
pathways remain active in primary cancers [22] . results are consistent with the original hypothesis,
or should they cover the same or different prostate
The final argument against designer cell lines is that
of clonal selection. Prostate cancers are incredibly cancer phenotypes? One sample each from castration
heterogeneous, containing multiple sub-clones resistant and hormone sensitive cells is by no means
with a restricted number of mutations, but with statistically significant, however the analysis of 10-12
distinct differentiated states and epigenetic levels tumors of a similar Gleason grade in patients with a
of control. To treat all of these with a single drug is similar hormone naïve background should provide
over ambitious. However, to derive models such as statistically relevant results, which also can reflect, in
those previously described, the scientist is reliant on their diversity, the patient specific variation we see in
the ability of some or all of these cancer cell types to responses to many drugs [23] . Although clonal selection
grow in the laboratory. As a population of cells begins can also be an argument against primary cultures,
to grow from a cancer, those which initiate growth first they at least do have a heterogeneous phenotype
are inevitably going to dominate the final culture by (several cell subpopulations are represented), they
means of the exponential growth of cells. Exponential can be differentiated in 2D culture to give rise to other,
growth means that even within 3-4 days there could be more luminal, cell populations and when routinely
8 to 16 fold more of a fast growing cell compared to a used at low passages the amount of time-dependent
slower growing cell in the same population. Thus long selection pressure is reduced.
264 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ November 17, 2017