Introduction
Non-melanoma skin cancers are the predominant types
of skin cancer, encompassing basal cell carcinoma and squamous cell
carcinoma (SCC) (1). Cutaneous SCC
(cSCC) is identified as the second most common skin cancer, next to
basal cell carcinoma (2). It
develops from precursory lesions known as actinic keratosis and has
the potential to metastasize. The principal risk factor for cSCC is
exposure to ultraviolet (UV) solar radiation, where total lifetime
exposure plays a crucial role (3).
The primary treatment method is surgical removal, although
radiation therapy may be considered for certain patients (4). Individuals with weakened immune
systems face an increased risk of developing cSCC, and while
metastasis is uncommon in areas exposed to the sun, it is a more
critical concern for those who are immunocompromised (5).
Within the field of cSCC research, mouse models are
invaluable for investigating the origins and metastatic
capabilities of the disease, as well as responses to treatments
(6). Specifically, the dual-stage
carcinogenesis protocol, which involves the use of
7,12-dimethylbenz(a)anthracene (DMBA) followed by
12-O-tetradecanoylphorbol-13-acetate, has been crucial in
understanding tumor development and identifying genetic mutations
commonly associated with cSCC (7).
Drug resistance in carcinomas can arise from
numerous mechanisms, many of which remain unclear. A notable
portion of these resistance processes is linked to the multidrug
resistance (MDR) phenotype, which is facilitated by drug efflux
pumps. These pumps are part of the ATP-binding cassette (ABC)
protein family. P-glycoprotein (P-gp), encoded by the MDR1 gene,
was the initial ABC transporter discovered to contribute to MDR
(8). On the other hand, the
multidrug resistance-associated protein (MRP-1), encoded by the
ABCC-1 gene on chromosome 16p13.1, exhibits high expression levels
in some types of tumors compared to healthy tissues (9). Additionally, cell lines with elevated
expression levels of MRP-1 have exhibited resistance to several
anticancer drugs, including doxorubicin, vincristine, etoposide and
cisplatin (10).
Recent advances in the systemic treatment of
advanced-stage cSCC have notably reshaped the therapeutic
landscape, including the use of immune checkpoint inhibitors and
targeted therapies (11-15).
These therapeutic advances underscore the need for a more in-depth
understanding of the molecular underpinnings of cSCC progression,
particularly in relation to drug resistance mechanisms, such as
those involving ABC transporters and glucose metabolism. It is
considered that older cytotoxic regimens (e.g., platinum-based
chemotherapy) exhibited limited efficacy and marked toxicity
(16). The recent targeted
therapies, including EGFR inhibitors, and particularly immune
checkpoint inhibitors,such as cemiplimab and pembrolizumab, have
demonstrated improved objective response rates and survival
benefits, often with better tolerability. The neoadjuvant use of
these agents is also emerging as a promising approach in high-risk
resectable cSCC (17).
In this evolving systemic treatment scenario,
understanding molecular pathways involved in tumor metabolism and
drug resistance, such as the expression of glucose transporter 1
(GLUT-1), MRP-1 and P-gp, remains essential. Such insights could
inform therapeutic stratification, identify biomarkers of response
or resistance, and support the rational combination of local and
systemic therapies.
GLUT-1, a key member of this family (GLUT protein
family), plays a critical role in tumor cells by modulating
glycolysis and cells' glucose uptake. Several studies have
consistently demonstrated that GLUT-1 overexpression, which is
linked to an increased glucose metabolism, is prevalent in various
human solid tumors (18-21).
In the majority of cases, GLUT-1 overexpression is associated with
greater tumor aggressiveness and poorer clinical outcomes.
Inhibiting GLUT-1, through reduced glycolysis and glucose uptake
rates, leads to cell-cycle arrest and inhibition of cancer cell
growth both in vitro and in vivo (22). Moreover, GLUT-1 overexpression has
been linked to resistance to radiotherapy and worse outcomes in SCC
(23).
As regards the analysis of the markers, P-gp, MRP-1
and GLUT-1, in relation to the diagnosis of cSCC, there are minimal
data available. Specifically, for GLUT-1, one study on skin SCC
reported that its expression was associated with the degree of
cancer differentiation (18). This
observation aligns with other data pertaining to oral SCC (24,25).
A high expression of GLUT-1 and GLUT-3 in oral SCC appears to be
linked to a poor prognosis. To the best of our knowledge, no study
to date has specifically addressed the role of P-gp in the
diagnosis of cSCC; however, in conjunction with the assessment of
other parameters, it may enhance the diagnosis of oral SCC and
appears to have relevant prognostic potential in esophageal SCC
(26,27).
As regards MRP-1, beyond its undisputed contribution
to resistance to therapy, no prognostic capability has been found
for cutaneous, or other types of SCC. Moreover, no prognostic
capability in relation to the diagnosis of SCC was traced
concerning the combination of P-gp, MRP-1 and GLUT-1.
In the present study, in a hairless murine model of
induced SCC of the skin, the expression levels of the markers P-gp,
MRP1, and GLUT-1 were determined in cutaneous SCC and in the
adjacent UV-irradiated and distant non-irradiated skin serving as a
control. The aim of the present study was to observe these
parameters and assess their relative diagnostic and prognostic
value in cutaneous SCC.
Materials and methods
Reagents
DMBA and acetone, both exceeding 95% purity, were
sourced from MilliporeSigma.
Animals
A total of 5 SKH-hr1 type hairless mice, aged 12 to
15 weeks and with an average weight of 26.87±1.93 g, were used to
examine the induction of cutaneous SCC and the estimation of marker
expression. These mice were obtained from the breeding facilities
of the Section of Pharmaceutical Technology, Small Animal
Laboratory, National and Kapodistrian University of Athens (Athens,
Greece), holding a European License Code of EL 25 BIO-BR 06. The
care provided to these animals was in strict compliance with the
guidelines set forth by the European Council Directive 2010/63/EU.
The mice had unlimited access to solid pellets (Keramaris Brothers
& Co., General Partnership, Athens, Greece) and fresh
water.
The mice were housed in an environment where the
temperature was maintained at 24±1˚C and the humidity at 40±10%. A
1-week acclimatization period was allowed prior to the initiation
of the experiments. The lighting regimen consisted of alternating
12 h of light and 12 h of darkness, using fluorescent lamps
specifically chosen to emit no measurable UV radiation.
The experimental protocol received approval from the
National Peripheral Veterinary Authority's Animal Ethics Committee,
under the license no. K/4243/18-10-02. All procedures were
performed in compliance with the ARRIVE Guidelines. Following the
induction of carcinogenesis, the animals were euthanatized by
cervical dislocation according to the AMVA guidelines and skin
samples were obtained.
UV exposure
A Xenon lamp of 1,000 W (model 6269) housed in an
Arc Lamp Housing (model 66020-M) and powered by a Universal Power
Supply (model 68820) from Oriel Instruments provided
solar-simulated UV radiation (290-400 nm). This radiation was
filtered through wavelength-specific filters, and the irradiance
was verified prior to each experiment using a Goldilux Smart Meter
(model 70239) from Oriel Instruments.
Induction of skin carcinogenesis by
DMBA and UV radiation
The method for initiating skin carcinogenesis with
DMBA and promoting it with UVR followed previously reported
procedures (7). In brief, the back
of each mouse received five topical applications of DMBA solution
(0.015% in acetone), 0.2 ml each, at 5-day intervals. Following the
final DMBA treatment, the mice were subjected to UVA (8.5
mW/cm2) and UVB (8 mW/cm2) radiation for 5
weeks, with 5 sessions per week. The initial exposure was set to a
median erythemal dose (MED) of 32 mJ/cm2 (7), with a 25% increase each subsequent
week to skip skin thickening.
Skin sampling and homogenization
From each animal, three distinct skin samples were
obtained: One cancerous (cSCC), one healthy, but adjacent to the
cSCC (distance of ~1-2 mm), and one healthy, but distant (distance
of ~30 mm). Following their classification, all samples were
weighed and subsequently homogenized along with a 0.05% Tween-20
solution in PBS using a pyrex glass 21x150 mm homogenizer from
Corning Inc.
Fluorometric measurements
To ensure assay reliability and reproducibility,
several quality control measures were implemented throughout the
immunochemical protocol. All antibodies, both primary [GLUT-1 A-4
(sc-377228), MRP-1 QCRL-1 (sc-18835) and P-gp G3PP/P-GP E-10
(sc-390883)], as well the secondary antibody (mouse anti-rabbit
IgG-CFL 488: sc-516248), were purchased from Santa Cruz
Biotechnology, Inc. with established specificity.
Phosphate-buffered saline (PBS) was provided by MilliporeSigma,
while Tween-20 was supplied by ICN Biomedicals, Inc. MaxiSorb
96-well plates were purchased by Nalge Nunc (Thermo Fisher
Scientific, Inc.). The primary antibodies were immobilized on
high-affinity Maxisorb 96-well plates at a standardized dilution
(1:250), under controlled pH conditions (carbonate buffer, pH 9.6)
and temperature (4˚C for 12-16 h).
Following each incubation step, the wells were
rigorously washed six times with PBS containing 0.05% Tween-20 to
remove non-specifically bound material. The secondary antibodies
used included fluorescently labeled anti-IgG conjugates. The
secondary antibodies used included fluorescently labeled anti-IgG
conjugates (mouse anti-rabbit IgG-CFL 488), applied at a dilution
of 1:400, enabling quantification through fluorescence
emission.
Fluorescence measurements were performed using the
Fluostar Galaxy fluorometer, with excitation and emission
wavelengths set at 485 and 520 nm, respectively. Each sample was
normalized for both background signal (blank) and total protein
concentration (mg/ml) using the following formula: A=(S-B)/Cs,
where S is the signal from the sample, B is the corresponding blank
value, and Cs is the sample protein concentration. This
normalization produced values in relative fluorescence units (RFUs,
ml/mg), enabling consistent comparisons across samples.
All samples were processed under uniform conditions
using the same batches of reagents and standardized incubation
protocols. This approach ensured intra-assay consistency and
minimized procedural variability.
In brief, from each animal, three distinct skin
samples were measured. Maxisorb plates were coated with 100 µl
primary antibody, one for each protein, dissolved in a carbonate
buffer solution (pH 9.6) at a 1:250 ratio. The preparations were
sealed with parafilm and stored at 4˚C for a period of 12-16 h.
Subsequently, the excess of the primary antibody solution was
removed, and following six washes with 300 µl of a 0.05% Tween-20
in PBS solution, 100 µl of homogenized tissue sample was added and
incubated for 30 min at room temperature, followed by six further
washes and the addition of 100 µl of the secondary antibody
suspension, and was subsequently allowed to stand at room
temperature for a further 30 min. The plates were then washed six
more times before incubating with 100 µl of the previously
described fluorescein-tagged secondary antibodies for 15 min. After
removing the contents of the wells and performing four consecutive
washes, 100 µl washing solution (PBS, MilliporeSigma) was added to
each well. The plates were then placed in a fluorometric device for
the corresponding measurements. During these measurements, the
emission filter of the device was set to 520 nm, while the
excitation filter was adjusted to 485 nm. The resulting values are
expressed in RFU/tissue mg.
Statistical analysis
Within-subject differences across three tissue types
were analyzed (cSCC tumor, adjacent and distant) using a
non-parametric repeated-measures approach (Friedman test) given
non-normal distributions in multiple outcomes. Post hoc pairwise
comparisons were performed with the Durbin-Conover procedure.
Global Friedman P-values and adjusted pairwise P-values are
presented. Analyses were conducted in Jamovi Cloud (https://www.jamovi.org). All analyses and graphical
representations were conducted using GraphPad Prism 8.4.2
(Dotmatics). A P-value <0.05 was considered to indicate a
statistically significant difference. To assess the adequacy of the
sample size, a post hoc statistical power analysis was conducted
using G*Power (version 3.1.9.7). The effect sizes (Cohen's f) for
each protein were calculated based on the mean and standard
deviation values across the three tissue types (cancerous, adjacent
and distant).
Results
Post hoc statistical power
analysis
Post hoc (observed) power, computed for the global
Friedman tests using Kendall's W as the effect-size proxy,
indicated moderate-to-large effects (MRP-1, W~0.39; P-gp, W~0.52;
GLUT-1, W~0.54). At α=0.05, the corresponding observed powers were
~0.41 (MRP-1), ~0.52 (P-gp) and ~0.54 (GLUT-1), reflecting limited
sensitivity at n=5. Prospective calculations suggest that ~13
(MRP-1), n~10 (P-gp) and n~9 (GLUT-1) would be required to achieve
~80% power (k=3 repeated measures).
DMBA-UV-induced mouse skin
carcinogenesis
The development of tumors observed in the present
study aligns with findings from prior research involving hairless
mice, where tumors initially manifest as actinic keratosis and then
benign papillomas. These elements then evolve into more aggressive
forms before culminating in squamous cell carcinomas, mirroring the
progression pattern documented in earlier studies (28).
MRP-1 assay
As illustrated in Fig.
1, for MRP-1 the global Friedman test did not indicate
differences across tissues (χ2=3.89, df=2, P=0.143). In
pairwise comparisons, we observed a trend toward higher expression
in cancer vs. distant tissue (P_adj=0.075) and no difference for
adjacent vs. distant (P_adj=0.100), without reaching statistical
significance after correction for multiple testing. This suggests a
possible modest elevation of MRP-1 in tumor-proximal tissues,
particularly cancer vs. distant, that did not meet conventional
significance, likely reflecting limited power in this small
exploratory cohort (n=5).
P-gp assay
In the analysis of P-gp expression (Fig. 2), the Friedman test suggested an
overall trend (χ2=5.20, df=2, P=0.074; W=0.52). In
adjusted pairwise comparisons, the expression was higher in
adjacent than distant non-cancerous tissue (P_adj=0.021), whereas
cancer vs. distant showed only a borderline trend (P_adj=0.076) and
cancer vs. adjacent was not significant (P_adj=0.438). This pattern
suggests peritumoral upregulation of P-gp within the tumor field
(adjacent skin), while differences involving the tumor itself were
less consistent, an effect that will require larger samples to
verify.
GLUT-1 assay
The statistical analysis of GLUT-1 expression levels
across different skin tissue types revealed noteworthy outcomes, as
illustrated in Fig. 3. The global
test also revealed a trend (χ2=5.44, df=2, P=0.066;
W=0.54). Post hoc tests indicated higher expression in cancer vs.
distant (P=0.041), and adjacent vs. distant (P=0.021), whereas
cancer vs., adjacent was not significant (P=0.670). These findings
indicate that while GLUT-1 expression in the tumor itself is not
markedly different from surrounding or distant skin, perilesional
tissue exhibits significantly higher GLUT-1 levels compared to
distant normal skin, suggesting a metabolic adaptation in skin
adjacent to the tumor.
Discussion
MRP-1, P-gp and GLUT-1 expression dynamics
associated with cSCC revealed a complex interplay of statistical
variances among different tissue groups. Notably, despite the
relatively small sample size, certain statistically significant
variances have emerged, rendering these findings particularly
compelling. The post hoc power analysis (Friedman framework, effect
size via Kendall's W) indicated moderate-to-large effects overall
but limited sensitivity at n=5 (observed power ~0.41-0.54 at
α=0.05). In line with this, pairwise differences reached
statistical significance for GLUT-1 (cancer vs. distant; adjacent
vs. distant) and for P-gp (adjacent vs. distant), whereas MRP-1
exhibited only a trend and did not reach significance. Thus, the
lack of significance in some comparisons, particularly for MRP-1,
may reflect insufficient power rather than absence of an effect.
These observations merit further exploration within the context of
cSCC development and its interaction with adjacent tissues.
Especially considering that the elevated expression of P-gp, GLUT-1
and MRP-1 proteins observed has already been reported in the
literature of squamous cell carcinomas (9,18,29,30).
A pivotal aspect of the analysis was the discovery
that, progressing from the core site of cSCC towards the peripheral
regions, there was an observable trend: The expression of
transporter proteins in adjacent normal tissues to cancer appears
to be similar to that of cancerous tissues. However, in distant
normal tissues from the cancer site, the expression is
significantly reduced or even absent. The above model does not have
strong statistical significance for all the transporters studied.
Such variance underscores the distinct regulatory mechanisms and
roles which these transporters play within the tumor
microenvironment of cSCC, suggesting varied responses to oncogenic
stimuli. Indeed, the expression of GLUT-1 has been reported to
correlate with the various stages of squamous cell carcinoma
(18).
Although the global Friedman test for P-gp did not
reach conventional significance (χ2=5.20, P=0.074), the
adjusted pairwise comparison indicated higher expression in
adjacent than distant non-cancerous skin (p_adj=0.021). The cancer
vs. distant contrast exhibited only a borderline trend
(p_adj=0.076), while cancer vs. adjacent was not significant
(p_adj=0.438). Given the small sample (n=5), post hoc power under
the Friedman framework was modest (observed power ~0.52 at α=0.05;
Kendall's W≈0.52), indicating limited sensitivity to detect modest
effects. Prospective calculations suggest that ~10 subjects would
be required to achieve ~80% power for an effect of this magnitude.
Larger cohorts are therefore warranted to determine whether the
observed pattern reflects a true biological difference.
Despite the variations in protein expression
relative to the distance from the cSCC site not uniformly reaching
statistical significance, the consistent trend across all three
studied proteins is notable. The findings suggest that the regions
of healthy skin immediately adjacent to cSCC sites, which did not
show signs of actinic keratosis, exhibited altered metabolic
activity. This observation is pivotal, as it potentially unveils a
precancerous alteration of the tissue that remains invisible to the
naked eye, thereby identifying these regions as possibly being at
an elevated risk for future oncogenic transformation. These results
can provide a molecular-level perspective on the aggressive
locoregional behavior of cSCC, observed locally as an extensive
invasion into neighboring tissues (24).
This revelation bears notable clinical implications,
particularly in the prognosis and therapeutic strategies for cSCC.
It suggests the necessity of considering a broader therapeutic
interest area around the tumor, acknowledging that the adjacent
tissues, though not exhibiting the actinic keratosis phenotype, may
still be undergoing critical, precancerous changes. Such an
approach could fundamentally shift the paradigms of surgical or
radiological interventions, advocating for the inclusion of a wider
margin around the tumor to address areas with potential
precancerous activity. This strategy aims to enhance treatment
efficacy and possibly reduce the recurrence rates of cSCC,
underscoring the critical importance of incorporating molecular and
cellular insights into clinical decision-making processes.
The present study has several limitations which
should be mentioned. Notably, the small sample (n=5 SKH-hr1
hairless mice) limits generalizability and increases the risk of
type II error. While pairwise contrasts reached significance for
GLUT-1 (cancer vs. distant; adjacent vs. distant) and for P-gp
(adjacent vs. distant), MRP-1 did not reach significance and
several comparisons only exhibited trends. A post hoc power
assessment under the Friedman framework indicated modest observed
power (~0.41-0.54 at α=0.05), and prospective calculations suggest
that larger cohorts would be required, particularly for detecting
modest effects in P-gp. The small sample also contributed to
variability, as reflected in wide dispersions around the estimates.
Accordingly, the findings should be interpreted as exploratory and
warrant confirmation in larger studies with orthogonal
validation.
Furthermore, no histological or immunohistochemical
images were included to support the identification of cSCC and its
distinction from adjacent or distant normal tissues. While the
experimental model used is well established and tumor formation was
confirmed macroscopically, the absence of microscopic validation
using standard markers (such as Ki-67, CK5/6, p63 or p40) prevents
a detailed morphological characterization of the lesions.
Similarly, the lack of immunohistochemical localization of the
target proteins (P-gp, MRP-1 and GLUT-1) limits the ability to
correlate their expression with specific tissue structures or cell
populations.
In addition, the methodology employed assessed total
protein expression via a fluorometric solid-phase immunoassay,
which, although appropriate for relative quantification, does not
provide information about the functional activity of the
transporters. Functional assays to measure efflux capacity or
glucose uptake would be necessary to confirm the biological
relevance of the observed expression levels. Similarly,
complementary techniques, such as western blot analysis were not
performed to validate the ELISA-based measurements.
The present study should therefore be considered an
exploratory, hypothesis-generating study that provides preliminary
insight into the expression gradients of drug-resistance and
metabolic transporters in UV-induced cSCC. The model did not
include any pharmacological treatment, and therefore reflects
transporter expression under carcinogenic rather than therapeutic
pressure. This is a critical distinction, as the expression and
activity of proteins, such as P-gp are often modulated in response
to chemotherapy.
Despite these limitations, the present study
highlights biologically meaningful trends and suggests that
membrane transporter expression in cSCC and its periphery may
represent an early molecular shift relevant to carcinogenesis, with
potential diagnostic or prognostic value. The present study also
aimed to contribute to the growing body of research seeking to
elucidate the molecular microenvironment of cSCC by demonstrating
differential expression patterns of key membrane transporters not
only within tumor tissue, but also in histologically
normal-appearing adjacent skin. The findings presented herein
underscore the presence of subclinical molecular alterations that
may precede visible pathology.
The potential of this approach lies in its
translational value. Following validation in larger preclinical and
clinical cohorts, these transporters may serve as biomarkers for
field cancerization, aiding clinicians in defining surgical margins
more precisely or identifying areas of skin at high risk for
malignant transformation. This highlights the concept of field
cancerization, a process by which cumulative UV exposure induces
molecular alterations in broader tissue zones, increasing
susceptibility to malignancy (31,32).
From a surgical perspective, while extending margins
indiscriminately is often unfeasible due to anatomical or cosmetic
constraints, our data may support more personalized surgical
planning, especially in high-risk or recurrent cases.
Additionally, alternative therapeutic approaches
could be explored. These include the application of targeted
photodynamic therapy in the peritumoral zone (33), the use of topical metabolic
inhibitors in clinically normal yet molecularly altered skin
(34,35), or the implementation of molecular
imaging tools, such as PET tracers targeting GLUT-1, to better
delineate high-risk margins (36).
While preliminary, such interventions could complement standard
care by addressing subclinical disease spread. It is not
exaggerated to assume that this field will evolve within the next 5
years, towards personalized cutaneous oncology, where local and
systemic therapeutic decisions will be guided not only by histology
but also by molecular and metabolic profiling. Research such as the
present study aims to lay foundational research hypotheses for such
approaches, by identifying early and subtle biological shifts at
the tumor periphery.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The data generated in the present study may be
requested from the corresponding author.
Authors' contributions
GP and MCR were involved in the conception and
design of the study. GP and MK performed the experiments,
measurements and data collection. GP, CB, AV and MCR were involved
in the analysis and interpretation of the results. AV drafted the
manuscript. AV, CB, MCR reviewed the manuscript. All authors have
read and approved the final version of the manuscript. GP, AV and
MCR confirm the authenticity of all the raw data.
Ethics approval and consent to
participate
Mice were obtained from the breeding facilities of
the Small Animal Laboratory at the School of Pharmacy, adhering to
European License Code EL 25 BIO 06, in strict compliance with the
guidelines outlined in European Council Directive 2010/63/EU. The
procedures were conducted in accordance with the National
Peripheral Veterinary Authority's Animal Ethics Committee license
number K/4243/18-10-02 and adhered to the ARRIVE Guidelines.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
References
|
1
|
Linares MA, Zakaria A and Nizran P: Skin
Cancer. Prim Care. 42:645–659. 2024.
|
|
2
|
Verdaguer-Faja J, Toll A, Boada A,
Guerra-Amor Á, Ferrándiz-Pulido C and Jaka A: Management of
cutaneous squamous cell carcinoma of the scalp: The role of imaging
and therapeutic approaches. Cancers (Basel). 16(664)2024.PubMed/NCBI View Article : Google Scholar
|
|
3
|
Howell JY and Ramsey ML: Squamous Cell
Skin Cancer. 2023 Jul 31. In: StatPearls (Internet). StatPearls
Publishing, Treasure Island, FL, 2024.
|
|
4
|
Jansen P, Lodde GC, Griewank KG, Hadaschik
E, Roesch A, Ugurel S, Zimmer L, Livingstone E and Schadendorf D:
Management of partial and non-responding cutaneous squamous cell
carcinoma. J Eur Acad Dermatol Venereol. 36 (Suppl 1):S29–S34.
2022.PubMed/NCBI View Article : Google Scholar
|
|
5
|
Yuan S, Zhu T, Wang J, Jiang R, Shu A,
Zhang Z, Zhang P, Feng X and Zhao L: miR-22 promotes
immunosuppression via activating JAK/STAT3 signaling in cutaneous
squamous cell carcinoma. Carcinogenesis. 44:549–561.
2023.PubMed/NCBI View Article : Google Scholar
|
|
6
|
Kumah E and Bibee K: Modelling cutaneous
squamous cell carcinoma for laboratory research. Exp Dermatol.
32:117–125. 2023.PubMed/NCBI View Article : Google Scholar
|
|
7
|
Kyriazi M, Yova D, Rallis M and Lima A:
Cancer chemopreventive effects of Pinus Maritima bark extract on
ultraviolet radiation and ultraviolet
radiation-7,12,dimethylbenz(a)anthracene induced skin
carcinogenesis of hairless mice. Cancer Lett. 237:234–241.
2006.PubMed/NCBI View Article : Google Scholar
|
|
8
|
Robinson K and Tiriveedhi V: Perplexing
role of P-glycoprotein in tumor microenvironment. Front Oncol.
10(265)2020.PubMed/NCBI View Article : Google Scholar
|
|
9
|
Zhang B, Liu M, Tang HK, Ma HB, Wang C,
Chen X and Huang HZ: The expression and significance of MRP1, LRP,
TOPOIIβ, and BCL2 in tongue squamous cell carcinoma. J Oral Pathol
Med. 41:141–148. 2012.PubMed/NCBI View Article : Google Scholar
|
|
10
|
Lu JF, Pokharel D and Bebawy M: MRP1 and
its role in anticancer drug resistance. Drug Metab Rev. 47:406–419.
2015.PubMed/NCBI View Article : Google Scholar
|
|
11
|
Sahin TK, Ayasun R, Rizzo A and Guven DC:
Prognostic value of neutrophil-to-eosinophil ratio (NER) in cancer:
A systematic review and meta-analysis. Cancers (Basel).
16(3689)2024.PubMed/NCBI View Article : Google Scholar
|
|
12
|
Guven DC, Erul E, Kaygusuz Y, Akagunduz B,
Kilickap S, De Luca R and Rizzo A: Immune checkpoint
inhibitor-related hearing loss: A systematic review and analysis of
individual patient data. Support Care Cancer.
31(624)2023.PubMed/NCBI View Article : Google Scholar
|
|
13
|
Rizzo A, Mollica V, Marchetti A, Nuvola G,
Rosellini M, Tassinari E, Molina-Cerrillo J, Myint ZW, Buchler T,
Monteiro FSM, et al: Adjuvant PD-1 and PD-L1 inhibitors and
relapse-free survival in cancer patients: The MOUSEION-04 study.
Cancers (Basel). 14(4142)2022.PubMed/NCBI View Article : Google Scholar
|
|
14
|
Mollica V, Rizzo A, Marchetti A, Tateo V,
Tassinari E, Rosellini M, Massafra R, Santoni M and Massari F: The
impact of ECOG performance status on efficacy of immunotherapy and
immune-based combinations in cancer patients: The MOUSEION-06
study. Clin Exp Med. 23:5039–5049. 2023.PubMed/NCBI View Article : Google Scholar
|
|
15
|
Guven DC, Sahin TK, Erul E, Rizzo A, Ricci
AD, Aksoy S and Yalcin S: The association between albumin levels
and survival in patients treated with immune checkpoint inhibitors:
A systematic review and meta-analysis. Front Mol Biosci.
9(1039121)2022.PubMed/NCBI View Article : Google Scholar
|
|
16
|
Aboul-Fettouh N, Morse D, Patel J and
Migden MR: Immunotherapy and systemic treatment of cutaneous
squamous cell carcinoma. Dermatol Pract Concept. 11 (Suppl
2)(e2021169S)2021.PubMed/NCBI View Article : Google Scholar
|
|
17
|
Spadafora M, Paganelli A, Raucci M, Kaleci
S, Peris K, Guida S, Pellacani G and Longo C: Neoadjuvant
immunotherapy in cutaneous squamous cell carcinoma: Systematic
literature review and state of the art. Cancers.
17(637)2025.PubMed/NCBI View Article : Google Scholar
|
|
18
|
Abdou AG, Eldien MM and Elsakka D: GLUT-1
expression in cutaneous basal and squamous cell carcinomas. Int J
Surg Pathol. 23:447–453. 2015.PubMed/NCBI View Article : Google Scholar
|
|
19
|
Zhang Y and Wang J: Targeting uptake
transporters for cancer imaging and treatment. Acta Pharm Sin B.
10:79–90. 2020.PubMed/NCBI View Article : Google Scholar
|
|
20
|
Kunkel M, Moergel M, Stockinger M, Jeong
JH, Fritz G, Lehr HA and Whiteside TL: Overexpression of GLUT-1 is
associated with resistance to radiotherapy and adverse prognosis in
squamous cell carcinoma of the oral cavity. Oral Oncol. 43:796–803.
2007.PubMed/NCBI View Article : Google Scholar
|
|
21
|
Meyer HJ, Wienke A and Surov A:
Associations between GLUT expression and SUV values derived from
FDG-PET in different tumors-A systematic review and meta analysis.
PLoS One. 14(e0217781)2019.PubMed/NCBI View Article : Google Scholar
|
|
22
|
Li F, He C, Yao H, Liang W, Ye X, Ruan J,
Lin L, Zou J, Zhou S, Huang Y, et al: GLUT1 regulates the tumor
immune microenvironment and promotes tumor metastasis in pancreatic
adenocarcinoma via ncRNA-mediated Network. J Cancer. 13:2540–2558.
2022.PubMed/NCBI View Article : Google Scholar
|
|
23
|
Ancey PB, Contat C, Boivin G, Sabatino S,
Pascual J, Zangger N, Perentes JY, Peters S, Abel ED, Kirsch DG, et
al: GLUT1 expression in tumor-associated neutrophils promotes lung
cancer growth and resistance to radiotherapy. Cancer Res.
81:2345–2357. 2021.PubMed/NCBI View Article : Google Scholar
|
|
24
|
Harshani JM, Yeluri S and Guttikonda VR:
Glut-1 as a prognostic biomarker in oral squamous cell carcinoma. J
Oral Maxillofac Pathol. 18:372–378. 2014.PubMed/NCBI View Article : Google Scholar
|
|
25
|
Eckert AW, Lautner MH, Taubert H, Schubert
J and Bilkenroth U: Expression of Glut-1 is a prognostic marker for
oral squamous cell carcinoma patients. Oncol Rep. 20:1381–1385.
2008.PubMed/NCBI
|
|
26
|
Kelley DJ, Pavelic ZP, Gapany M, Stambrook
P, Pavelic L, Gapany S and Gluckman JL: Detection of P-glycoprotein
in squamous cell carcinomas of the head and neck. Arch Otolaryngol
Head Neck Surg. 119:411–414. 1993.PubMed/NCBI View Article : Google Scholar
|
|
27
|
Aloia TA, Harpole DH Jr, Reed CE, Allegra
C, Moore MB, Herndon JE II and D'Amico TA: Tumor marker expression
is predictive of survival in patients with esophageal cancer. Ann
Thorac Surg. 72:859–866. 2001.PubMed/NCBI View Article : Google Scholar
|
|
28
|
Gallagher CH, Canfield PJ, Greenoak GE and
Reeve VE: Characterization and histogenesis of tumors in the
hairless mouse produced by low-dosage incremental ultraviolet
radiation. J Invest Dermatol. 83:169–174. 1984.PubMed/NCBI View Article : Google Scholar
|
|
29
|
Zhang S, Cao W, Yue M, Zheng N, Hu T, Yang
S, Dong Z, Lu S and Mo S: Caveolin-1 affects tumor drug resistance
in esophageal squamous cell carcinoma by regulating expressions of
P-gp and MRP1. Tumour Biol. 37:9189–9196. 2016.PubMed/NCBI View Article : Google Scholar
|
|
30
|
Pérez-Sayáns M, Somoza-Martín JM,
Barros-Angueira F, Diz PG, Rey JM and García-García A: Multidrug
resistance in oral squamous cell carcinoma: The role of vacuolar
ATPases. Cancer Lett. 295:135–143. 2010.PubMed/NCBI View Article : Google Scholar
|
|
31
|
Trock BJ, Leonessa F and Clarke R:
Multidrug resistance in breast cancer: A meta-analysis of
MDR1/gp170 expression and its possible functional significance. J
Natl Cancer Inst. 89:917–931. 1997.PubMed/NCBI View Article : Google Scholar
|
|
32
|
Dean M, Hamon Y and Chimini G: The human
ATP-binding cassette (ABC) transporter superfamily. J Lipid Res.
42:1007–1017. 2001.PubMed/NCBI
|
|
33
|
Ferini G, Palmisciano P, Forte S, Viola A,
Martorana E, Parisi S, Valenti V, Fichera C, Umana GE and
Pergolizzi S: Advanced or metastatic cutaneous squamous cell
carcinoma: The current and future role of radiation therapy in the
era of immunotherapy. Cancers (Basel). 14(1871)2022.PubMed/NCBI View Article : Google Scholar
|
|
34
|
Worley B, Harikumar V, Reynolds K, Dirr
MA, Christensen RE, Anvery N, Yi MD, Poon E and Alam M: Treatment
of actinic keratosis: A systematic review. Arch Dermatol Res.
315:1099–1108. 2023.PubMed/NCBI View Article : Google Scholar
|
|
35
|
Greif CS, Srivastava D and Nijhawan RI:
Janus kinase inhibitors and non-melanoma skin cancer. Curr Treat
Options Oncol. 22(11)2021.PubMed/NCBI View Article : Google Scholar
|
|
36
|
Binderup T, Knigge UP, Federspiel B,
Sommer P, Hasselby JP, Loft A and Kjaer A: Gene expression of
glucose transporter 1 (GLUT1), Hexokinase 1 and Hexokinase 2 in
Gastroenteropancreatic neuroendocrine tumors: Correlation with
F-18-fluorodeoxyglucose positron emission tomography and cellular
proliferation. Diagnostics (Basel). 3:372–384. 2013.PubMed/NCBI View Article : Google Scholar
|
