Download Review on FDG in Chemoresistance

Influence of chemoresistance and p53 status on Fluoro-2-deoxy-D-glucose
incorporation in cancer
Tim A D Smith
School of Medical Sciences (Biomedical Physics), University of Aberdeen,
Foresterhill, Aberdeen AB25 2ZD UK
Address for correspondence: Dr Tim Smith,
School of Medical Sciences (Biomedical Physics),
University of Aberdeen,
Foresterhill,
Aberdeen AB25 2ZD UK
Tel: +44 01224 553481
[email protected]
Running title: FDG in chemoresistance and p53
Key words: Fluoro-2-deoxy-D-glucose; chemoresistance; PET; p53
Summary
Both mutant p53 and chemoresistance are poor prognostic factors in cancer. Many
studies have examined the influence of these factors on FDG incorporation. Whilst
mutant p53 is associated with increased FDG incorporation, chemoresistance
especially when associated with P-glycoprotein is associated with decreased FDG
incorporation.
Introduction
Resistance of cancers to chemotherapy and the presence of p53 mutations are both
associated with poor prognosis. A considerable number of clinical studies have
examined the influence of these two factors on FDG incorporation with a view to
using FDG-PET as a non-invasive determinant of prognosis. The findings from these
studies are summarised below along with the in-vitro cell studies which help to
explain the respective associations between FDG incorporation, p53 status and
chemoresistance.
Resistance to chemotherapy
Cancer cure is frequently abrogated either by inherent, or acquired drug resistance. An
inherently resistant tumor is one that shows little or no sensitivity to therapeutic
agents without prior exposure to the drug in question. Acquired resistance is where
the tumor is initially sensitive to treatment but becomes increasingly unresponsive to
the agent. Even very responsive tumors can develop drug resistance during the course
of their treatment [1].
Each cancer cell has thousands of genetic errors [2] and some will induce differing
states of drug sensitivity. When the tumor is exposed to a specific chemotherapy
agent, cells resistance to the drug will dominate. Residual tumor disease postchemotherapy is often associated with the presence of subsets of cells resistant to the
chemotherapy agent [1,3]. For example patients with ovarian cancer have high
response rates to initial chemotherapy after cytoreductive surgery but most develop
resistance to chemotherapy during the course of their treatment [3].
Mechanisms of drug resistance
There are a number of mechanisms for drug resistance. These include changes in the
rate of drug uptake and efflux, altered drug metabolism, decreased drug-target
complex formation, enhanced DNA repair mechanisms [4].
Anticancer drugs enter cells by diffusion or trans-membrane transport proteins. Drug
resistance can result from modulation of membrane receptors e.g. the anti-folate
agents methotrexate and tomudex enter the cell via the reduced folate carrier (RFC)
and resistance to methotrexate has been shown to be associated with decreased
expression of RFC [5]. Some chemotherapeutics directly affect target molecules such
as the platinum drugs that interact directly with DNA. Resistance to platinum drugs
can be due to increased tumour cell levels of molecules that inactivate these
compounds such as glutathione [6]. Drugs such as 5fluorouracil (5FU) require
chemical modification. 5FU is anabolised to a thymidylate synthase inhibitor although
most 5FU is catabolised by dihydropyrimidine dehydrogenase (DPD) and 5FUresistant cells have been shown to express higher than normal levels of DPD and
increased levels of thymidylate synthase [5]. A further mechanism of resistance is
induced by changes in the protein target of some drugs e.g. resistance to paclitaxel
and docetaxel include acquired mutations at the drug binding site of tubulin and
differential expression of tubulin isoforms [7,8] Increased efflux of drugs including
taxanes and anthracyclines can result from expression of the ABC transporter proteins
such as P-glycoprotein. Multi drug resistance (MDR) is the state in which tumor cells
are resistant to a wide range of different chemotherapy drugs including doxorubicin
(an anthracycline), alkaloids (e.g colchicine) due to the presence of the plasma
membrane protein P-glycoprotein (P-gp). Changes in the apoptotic signal induction
pathways are also involved in chemotherapy-resistance [6].
P53 status, drug resistance and prognosis
To prevent neoplastic formation, cellular P53 protein responds to DNA damaging
cellular insults by either orchestrating DNA repair mechanisms or, where DNA
damage is irreparable, by induction of apoptosis pathways. In view of its crucial role
in maintaining DNA integrity p53 protein is referred to as the ‘Guardian of the
genome’. In the absence of cell stress p53 protein levels are low but X-rays, UV,
DNA-damaging chemotherapy drugs, DNA synthesis inhibitors, disruptors of
microtubule components, hypoxia, myc introduction into cell, depletion of
intracellular nucleotide precursor pools all cause increased p53 within minutes. Loss
of p53 function through mutation is associated with many cancer types [9]. Since
most anti-cancer chemotherapy works through induction of apoptosis, loss of p53
function through mutation is associated with resistance to some drugs including
doxorubicin [10] and cisplatin [11]. Further therapy response and survival have been
shown to be detrimentally influenced by p53 abnormality in patients with leukemia
[12], lymphoma [13] and epithelial ovarian cancer [14].
[18F]Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)
Positron emission tomography (PET) using the glucose analogue fluoro-2-deoxy-Dglucose (FDG-PET) is becoming a routine tool for probing tumour metabolism noninvasively and exploits the enhanced glucose utilization characterized by tumour
cells. The fluorinated glucose analogue,
18
F labelled glucose analogue, fluoro-2-
deoxy-d-glucose FDG is transported into tumour cells via a family of glucose
transporter proteins (Gluts) then phosphorylated by the enzyme hexokinase (HK) to
FDG-6-phosphate after which it undergoes little further metabolism (except
dephosphorylation by glucose-6-phosphatase (G-6-Pase)). Higher levels of HK and
Glut and low levels of G-6-Pase have been reported [15] in tumour tissue compared
with corresponding normal tissue. The use of serial FDG-PET scans of patients with
tumours during the course of chemotherapy has been demonstrated by many studies to
be a useful tool in cancer management [16]. Generally, compared with pre-treatment,
responding tumours show decreased FDG uptake within a few days of starting
chemotherapy.
FDG incorporation and resistance to chemotherapy
Sestabimi is a substrate for the P-gp pump and so the rate of efflux of 99mTc-sestabimi
can be used to diagnose MDR-related P glycoprotein expression in solid tumours
[17]. However the utility of FDG incorporation as an indicator of the MDR phenotype
has been investigated in a number of studies [18-20]. In each of these studies,
consisting respectively of 47 patients with untreated lung cancer [18], 35 patients with
intrahepatic cholangiocarcinoma (ICC) [19] and 70 patients with hepatocellular
carcinoma (HCC) [20] expression of P-gp, determined immunohistochemically and
found to negatively correlate with tumour SUV (standardised uptake value).
In-vitro studies [21-23] also showed that cells exhibiting the MDR phenotype
incorporate FDG at lower levels than MDR-negative control cells. Thus Lorke et al
[21] found that FDG incorporation by multi-drug resistant HT-29 colon carcinoma
cells grown in-vitro or as xenografts in SCID mice was lower compared with
incorporation by sensitive HT-29 cells whilst incubation of cells with inhibitors of Pgp showed that efflux of FDG by the P-gp is a mechanism responsible for decreased
FDG incorporation by cells expressing MDR. Recently Seo et al [22] compared FDG
incorporation by PLC/PRF/5 cells and doxorubicin-resistant P-gp expressing
PLC/DOR cells and found FDG incorporation to be lower in PLC/DOR cells
compared with PLC/PRF/5 cells. Treatment with the P-gp inhibitors Verapamil and
cepharanthine restored FDG uptake in PLC/DOR cells, but not in PLC/PRF/5 cells.
Yamada et al [23] have also shown by treating the multi-drug resistant melanoma cell
line SK-MEL 24 with inhibitors of Pgp that FDG is a substrate for the Pgp pump.
Another possible mechanism responsible for the lower FDG incorporation by MDR
positive tumour cells is decreased expression of glucose transporters. In a series of
colchicine-selected multidrug-resistant (MDR) human KB carcinoma cell lines MDR
resistant cells exhibit decreased glucose transport which correlated with the sensitivity
to the toxic effect of 2-deoxy-D-glucose [24].
Tumor resistance to 5FU has been shown to be directly associated with changes in
FDG incorporation [25] and to induce modifications in pathways associated with
FDG incorporation [26]. Cells can be selected for drug resistance by exposure to
increasing concentrations of the drug over a period of months or years. We previously
reported [25] that although glucose transport was increased in cells selected for
resistance to 5FU compared with sensitive control MCF-7 cells FDG incorporation by
the resistant cells was actually lower. Using the glucose transport inhibitor phloretin
we demonstrated that the decreased FDG incorporation by the resistant compared
with the sensitive cells was due to increased efflux of FDG via the glucose
transporters. Using a clone of T47D breast tumour cells selected for 5FU-resistance it
has also been shown that ATP-synthase activity is diminished in the resistant cells
when compared with WT cells [26].
Two studies have examined FDG incorporation by tumors resistant to tyrosine kinase
inhibitors [27, 28]. In one case two patients with gastrointestinal stromal tumors that
were resistant to imatinib were associated with low FDG incorporation [27]. Su et al
[28] determined FDG uptake by 4 NSCLC tumor lines with varying levels of
sensitivity to the EGFR kinase inhibitor gefitinib in-vitro or grown as xenografts in
nude mice during treatment with this compound. FDG incorporation was only found
to change in cells sensitive to the gefitinib. Western blot studies carried out on
cytosolic and membrane fractions indicated that this was due to translocation of
glucose transporters from the membrane to the cytosol in the sensitive tumor cells.
Not all studies have found differences in FDG incorporation between resistant and
non-resistant tumor cells. Treatment with paclitaxel increased FDG uptake to a similar
extent by WT human adenocarcinoma-derived ovarian cells (A2780) and cells that
had been selected for resistance to doxorubicin [29].
P53 and FDG incorporation
Patients with Li-Fraumeni syndrome (LFS) have an underlying germline mutation in
their p53 gene resulting in an inherited predisposition to a range of cancer types [30].
FDG-PET/CT has recently been used to screen for cancers in such patients [31]. Of
15 asymptomatic patients with LFS cancers were detected in 3 suggesting that FDGPET/CT could be utilised in the surveillance of such patients although the risks of
radiation exposure to at rick patients needs to be examined.
Loss of p53 has been shown to be associated with enhanced rates of glucose
utilisation by tumor cells [32] and many clinical studies have compared tumor FDG
incorporation (usually maximal SUV (standardised uptake value)) between patients
with wild type p53 tumours and patients with mutant P53. P53 protein content is
determined using immunohistochemistry and increased p53 expression is assumed to
be due to overexpression of mutant p53. Positive correlations between p53 expression
and FDG incorporation were observed in studies of 90 patients with colorectal cancer
[33], two studies of primary breast cancer consisting of 275 [34] and 86 patients [35],
two studies of non-small cell lung carcinoma (NSCLC) consisting of 149 [36] and 82
[37] patients respectively, 38 patients with cervical cancer [38], two studies of
patients with bone soft tissue sarcomas consisting of 63 [39] and 89 [40] patients
respectively. Further two small studies of patients with hepatocellular carcinoma
[41,42] showed that the lesions with the highest FDG incorporation expressed mutant
p53. Studies that have shown p53 expression not to be related to FDG incorporation
are in the minority and include a small study (19 patients) with ovarian cancer [43], or
in a study using a contrast ratio of lung tumor vs non-involved lung of 71 patients
with c-stage IA lung adenocarcinomas [44] and a study of 75 patients with breast
cancer [45]. Other studies [46] have compared FDG incorporation in tumors of
patients patients according to expression of tumor suppressor genes including p53 and
showed that the groups with aberrant tumor suppressor genes had a higher FDG
incorporation than did tumors without mutations in these genes
Several of these studies [33, 36, 38 and 39] also compared the protein expression of
glucose transporters and hexokinases with p53 status. Some found glut1 [33, 36, 39]
but not glut-3 [33] expression to be positively associated with p53 expression.
However tumur cells can express several different glucose transporters and their
expression does not necessarily correspond with glucose transport at the functional
level [47].
To determine the effect of abrogation of functional p53 on FDG incorporation by
tumor cells we transfected MCF-7 breast tumor cells with a dominant negative p53
construct [47]. FDG incorporation was found to be increased in the p53 abrogated
cells compared with wild-type MCF-7 cells. Using microarray we found that glucose
transporters 1, 8, and 10 were expressed in MCF-7 cells and HK I was the principal
HK in MCF-7 cells but was not differentially expressed at the messenger RNA level
in the dominant negative p53 clones, compared with WT cells. However, increased
HK activity was observed in both dominant negative p53 clones, compared with WT
MCF-7.
A further mechanism by which FDG incorporation could be increased in cells with
attenuated p53 levels is through a switch from aerobic to anaerobic respiration.
Pathways associated with p53 Matoba et al 2006 [48] showed that O2 consumption
was lower and lactate production higher in p53-/- compared with p53+/+ HCT116 cells
and that this was due to p53 controlling the synthesis of cytochrome c oxidase
required for the terminal step of the respiratory chain catalysing transfer of e- to O2.
Conclusions
Overall these results show that mutant p53 resulting in loss of cell p53 function is
associated with high levels of FDG incorporation. However resistance to
chemotherapy which is also a negative prognostic indicator is associated with
decreased FDG incorporation. This would suggest that the use of pre-treatment levels
of FDG incorporation alone cannot be utilised clinically as a measure of prognosis.
However in combination with p53 status, which can be determined using biopsy
derived tissue, FDG incorporation could be a useful predictor of chemoresistance
especially in patients with wild type p53 tumors.
In-vitro studies of FDG incorporation with both resistant and p53 largely correspond
with clinical findings attributing veracity to the use of in-vitro systems to investigate
and explain clinical phenomena.
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