50
in order to improve the diagnostic, prognosis, and treatments available today for
many diseases. The use of molecular and cellular biology techniques in epidemiologic research has initiated a new field called molecular epidemiology. Molecular
epidemiology studies the biological events that connect an environmental carcinogen with the occurrence of cancer by using biomarkers. Biomarkers allow to assess
exposure, internal dosage, biological effective dosage, altered structure/function,
invasive cancer diagnosis, tumor metastasis and prognosis, as well as susceptibility
(Chen and Hunter 2005). Currently, there are poor biomarkers for skin cancer diagnostics, progression, prognosis, and metastasis, factors which are of main interest in
secondary prevention (Greinert 2009). Few biomarkers are available to follow progression of cancer in patient populations and/or to guide decision-making with
respect to dose and administration schedule (Kirsch 2015). Thus, one of the benefits
of deepening the knowledge on the molecular events that are activated during the
DDR after UV radiation is to find better biomarkers to improve diagnosis tests,
predicting tumor response to both radiation and chemotherapy, and to develop more
precise skin cancer treatments.
4.2.3.1 DNA Repair Proteins as Markers for Skin Cancer
As it was explained in Sect. 4.2.2.2, following induction of lesions on the DNA,
cells activate a DDR in order to detect the lesions and repair them to allow the normal progression of the cell cycle. Thus, the expression of proteins involved in the
DDR may change during progression of healthy cells to malignancy (cancerous
cells) turning them into excellent biomarkers for diagnostic or prognosis of patients.
Researchers from dermatological and oncological departments have joined forces to
set up novel and more accurate skin cancer biomarkers based on the DDR activated
after UV radiation.
H2AX, a protein activated after DSBs formation – see Sect. 4.2.2.2 – has been
evaluated as possible biomarker. Whereas normal human melanocytes (skin cells
which produce the protective skin-darkening pigment melanin) displayed low-level
expression of activated H2AX (γH2AX), melanoma cell lines showed significantly
increased levels of this marker (Warters et al. 2005). Automated quantitative analysis (AQUA) and Tissue Studio are commercial technologies that use digitized
immunofluorescence microscopy images to quantify protein expression in defined
tissue compartments. In a work published in 2014, these algorithms were used to
quantify H2AX activation in several cells and tissues from the skin. After standardizing the system with normal human fibroblast cells, 40 melanoma cells lines and 22
metastatic melanoma tissues were analyzed. This software showed a high intensity
of γH2AX on melanoma cells. AQUA also revealed high γH2AX expression in
metastatic melanoma samples similar to that seen for the melanoma cell lines,
whereas the normal surrounding tissue had significantly lower γH2AX levels
(Nikolaishvilli-Feinberg et al. 2013). Another work reported positive γH2AX and
Chk2 stain for dysplastic nevi and positive γH2AX stain for melanomas, whereas
the surrounding normal skin did not (Gorgoulis et al. 2005). Thus, it is possible that
M. B. Federico
in order to improve the diagnostic, prognosis, and treatments available today for
many diseases. The use of molecular and cellular biology techniques in epidemiologic research has initiated a new field called molecular epidemiology. Molecular
epidemiology studies the biological events that connect an environmental carcinogen with the occurrence of cancer by using biomarkers. Biomarkers allow to assess
exposure, internal dosage, biological effective dosage, altered structure/function,
invasive cancer diagnosis, tumor metastasis and prognosis, as well as susceptibility
(Chen and Hunter 2005). Currently, there are poor biomarkers for skin cancer diagnostics, progression, prognosis, and metastasis, factors which are of main interest in
secondary prevention (Greinert 2009). Few biomarkers are available to follow progression of cancer in patient populations and/or to guide decision-making with
respect to dose and administration schedule (Kirsch 2015). Thus, one of the benefits
of deepening the knowledge on the molecular events that are activated during the
DDR after UV radiation is to find better biomarkers to improve diagnosis tests,
predicting tumor response to both radiation and chemotherapy, and to develop more
precise skin cancer treatments.
4.2.3.1 DNA Repair Proteins as Markers for Skin Cancer
As it was explained in Sect. 4.2.2.2, following induction of lesions on the DNA,
cells activate a DDR in order to detect the lesions and repair them to allow the normal progression of the cell cycle. Thus, the expression of proteins involved in the
DDR may change during progression of healthy cells to malignancy (cancerous
cells) turning them into excellent biomarkers for diagnostic or prognosis of patients.
Researchers from dermatological and oncological departments have joined forces to
set up novel and more accurate skin cancer biomarkers based on the DDR activated
after UV radiation.
H2AX, a protein activated after DSBs formation – see Sect. 4.2.2.2 – has been
evaluated as possible biomarker. Whereas normal human melanocytes (skin cells
which produce the protective skin-darkening pigment melanin) displayed low-level
expression of activated H2AX (γH2AX), melanoma cell lines showed significantly
increased levels of this marker (Warters et al. 2005). Automated quantitative analysis (AQUA) and Tissue Studio are commercial technologies that use digitized
immunofluorescence microscopy images to quantify protein expression in defined
tissue compartments. In a work published in 2014, these algorithms were used to
quantify H2AX activation in several cells and tissues from the skin. After standardizing the system with normal human fibroblast cells, 40 melanoma cells lines and 22
metastatic melanoma tissues were analyzed. This software showed a high intensity
of γH2AX on melanoma cells. AQUA also revealed high γH2AX expression in
metastatic melanoma samples similar to that seen for the melanoma cell lines,
whereas the normal surrounding tissue had significantly lower γH2AX levels
(Nikolaishvilli-Feinberg et al. 2013). Another work reported positive γH2AX and
Chk2 stain for dysplastic nevi and positive γH2AX stain for melanomas, whereas
the surrounding normal skin did not (Gorgoulis et al. 2005). Thus, it is possible that
M. B. Federico