POPESCU IULIAN PhD, MD, Clinical Department of Radio-Biology at the Fundeni Clinical Institute in Bucharest
e-mail: popdociul@yahoo.com
ALINA HALPERN PhD, SF.ŞTEFAN Hospital Bucharest
Classification of Lung Cancer (LC) is primarily
performed in morphological terms and in particular through immunohistochemical
methods.
Large cell carcinomas are a distinct group
of tumors within the non-small cell lung cancer.
The diagnosis of large cell lung cancer -
until now - is made by the exclusion of other forms of lung cancer (LC)
Wtihin large cell lung cancer it is observed
- at ultrastructural level - conformations of squamous or glandular
differentiation (1,2,3)
1) Large cell neuroendocrine carcinoma
2) Basaloid carcinoma
3) The lymphoepithelioma-like carcinoma
4) Large cell carcinoma with rhabdoid
phenotype
5) Clear cell carcinoma
LARGE CELL CARCINOMA
Histochemical
Markers
The cell of origin is not yet
known.
Large cell lung cancer is a form of low differentiated
cancer. Most of them express pan- cyto - keratin or the epithelial membrane
antigen (3,4,5 ) . At the same time, a higher percentage gets stained for cyto
- keratin7 (6.7 ).
Immunoreactivity for TTF1 is observed in
50% of cases in large cell lung cancers.TTF1 has specificity for CLARA cells
and pneumocytes II (8 ).
Approximately 30 % of the large
cell lung cancers show positivity for the markers of peripheral airway cells,
such as:
surfactant protein A ( SP -A) or CLARA cell
protein ( 10kd ) ( 9.10 )
Rossi et al (11 ) - by determining the
expression of CK7 , CK with high molecular weight, TTF1 and CD56 neural
adhesion molecule - divided the 45 cases of large cell lung cancers in 60% of
adenocarcinoma 22 % squamous form and 9% large cell cancers with neuroendocrine
differentiation .
In summary, large cell lung cancers have
ultrastructural appearance and histochemical phenotypes similar to lung
adenocarcinoma (ADC ) expressed both by TTF1 and Cyto - keratin7, like other ADC
markers such as: CEA , secretory component SP -A and B72.3 . Only a small group
has squamous appearance.
Molecular
Pathways and Prognostic Markers.
In general tumors with a high rate of
apoptosis have a shorter survival (12). In non-small cell lung cancer the Bcl-2
expression is related to a long survival of the tumor (13)
This is not seen in large cell lung cancer (14).
Immunoreactivity for EGFR is
observed in 56% of cases with large cell cancer. The high imunoreactivity for
EGFR is associated with an aggressive clinical behavior and short survival (15).
Study
of the Genes
The P53 gene mutations are common in large
cell lung cancer are and comparable with data from non-small cell lung cancer
P53 mutations are frequently mutated in
large cell lung cancer. They are found in exons 7,5 , and 8. Are more frequent
in smokers and patients with poorly differentiated lesions (16).
Tammehagi et al (17) in operated cases found
p53 mutations in a large percentage of 54% of the cases of non-small cell cancer.
The lowest percentage was in ADC (18).
The p16 gene inactivation is seen
in 71 % of cases in small cell lung cancer (19) and through the mechanism of hypermethilation
and a third in cases form of squamous cancer and ADC (58 %).
In large cell lung cancer is noticed the
p16 gene hypermethylation and p53 mutations,
the hypermethylation dominating against mutations , being the main mechanism of
inactivation (20)
In large cell lung cancer we have a
low expression of CyclinD1 (21) Kras. The Kras mutations have an important
role in ADC carcinogenesis. In the case of large cell lung cancer data are
variable. Out of 24 small cell lung cancer only one single case shown the Kras mutations.
Instead in ADC 41 cases of 144 had Kras mutations (22).
In
large cell lung cancer 25% of cases had RASSF1(3p gene) hypermethilation and
only 7% had Kras mutations and RASSF1(promoter) hypermethilation.
Chromosome
Issues
Most large cell tumors have clonal
aberrations (23). The most common aberrations involve
losses
in areas 1p, 1q, 3p, 6q, 7q and 17p
gains
in areas 5q, 7p and regions of the chromosomes 11,1 and 7
It is considered that the combination of
17p losses and abnormalities in chromosomes 1 and 6 observed in large cell
cancer resembles in kariotipic terms more with ADC than squamous form.
Many kariotipic changes of large cell lung
cancer are similar to those in non-small cell lung cancer (24)
Thus we chromosomal losses 9p,3p,6q,8p,9q,13q,17p,18q
19p,21q,22q
chromosomal
gains chromosome 7(7p and 7q),1q,3q and 5p
A significant presence is the 3p loss (loci
including RASSF1A and FHIT)
Losses in 9p involve the p16 gene
Losses in 17p involve the p53 (23,25,26 )
gene
Comparative
Genomic Hybridization
Analyzing by this method 30 cases (10 cases
of large cell cancer and 20 cases ADC) there have been observed that 26 cases had
alterations of the number of copies of the DNA (27)
It has been seen that specific
abnormalities of large cell lung cancer are similar to those seen in ADC (27).
Thus, in both we have
- DNA gains 8q,1q, 6pcen-21, 5p14
- DNA
losses 6qcen-23 and 17
In ADC gains dominated in 7pcen-21 and
losses in 8p and 18p
In large cell lung cancer and in non-small
cell lung cancer
-
losses 8p and 18p and
-
gains in 7p
On two cell lines in large cell lung have
been found
-
losses 15q12-q32,18q,6q,9 and 13q
- gains 5p,8q,15,6p,20q,1q21-11,2p,3q(28)
Loss
of Heterozygosity (LOH)
In general there is a similarity between the
large cell lung cancer and ADC
LOH in 3p is found in 3 carcinomas, but prevail
in small cell lung cancer neuroendocrine large cell lung cancer (29)
LOH in the area
of 5q23 is frequent in large cell lung cancer
LOH at TP53 and 13q14
is seen in all the 3 forms
LOH in the area of
12p is noticed in 50% of large cell lung
cancer and 96% in ADC cases
Activation – rare
– of the Kras mutations is seen in large cell lung cancer and in ADC, which
shows 12 LOH(23).
Finally in large
cell lung cancer prevail the cell cycle genes, genes related to DNA replication
and transcription factors. Genes that characterize the large cell lung cancer
are the same as seen in the embryonic development (the pseudo glandular and
canalicular period), while those of the lung adenocarcinoma are genes during
embryonic period when developing the
terminal bag and in alveolar stage (30). Genes associated with the proliferation
are observed in large cell lung cancer, whereas the genes related to the
differentiation is observed in lung adenocarcinoma, summarizing the normal ways
of developments (30).
NEUROENDOCRIN LARGE CELL CARCINOMA
Histochemical Issues
Large cell neuroendocrine cancer is stained
positively with
chromoguanin coloration
in 75% of cases,
synaptophyzin
coloration in 84%-100%,
coloration CD56 in
90%-100% (31,32,33,34)
In contrast to large cell lung cancer, it is
less frequently positive the cyto-keratin with high molecular weight and less
frequently Cyto-keratin7 (CK7)(32,33,35).
Similar to large cell lung cancer has
another positivity for TTF-1in 35%-70% of large cell neuro-endocrine lung cancer
(33,35,29)
TTF-1 is a marker linking also the tumor
type II pneumocytes cells to the lung CLARA cells.
The TTF-1 marker reactivity reflects either a significant
transcriptional disorder in an undifferentiated tumor, or reflects the
relations with neuroendocrine differentiation (1). It is unclear whether the
TTF-1 immunoreactivity of large cell lung cancer and large cell neuroendocrine lung
cancer origin can be construed with the same origin as in ADC- lung related or is
a connection still unknown, with neuroendocrine differentiation (1)
Molecular Pathways and Prognostic Markers
Generally tumors
with a high rate of apoptosis have a low survival (12).
Bcl2 is an
anti-apoptotic protein and is frequent in neuroendocrine large cell lung cancer
and in small cell lung cancer (36). The Bcl2 expression is related to a low
survival in non-small cell lung cancer (13), which does not happen in the large
cell lung cancer (37). In large cell neuroendocrine cancer we have a higher
frequency than in large cell lung cancer (12). In large cell neuroendocrine lung
cancer we have a ratio of Bcl-2-Bax larger than 1 similar to small cell lung
cancer (36).
The p53 pathway. The increase in p53 immuno
reactivity has been noticed in 65% in large cell neuroendocrine lung cancer compared
to 35% in large cell lung cancer (38).
Matrix-metalloproteinase-9, which is
responsible in invasion and also survenes in the process of metastasis, shows an increased
frequency in large cell lung neuroendocrine (38).
While we have frequent deletions in 3p area and a loss of heterozygosity (LOH) in the area 3.14,
the immune staining for the FHIT gene was negative in large cell neuroendocrine
lung cancer (25,26,39). The FHIT gene silencing is attributed to promoting the hypermethylation
process.
The large cell neuroendocrine lung cancer has an inverse
relationship between the expression of retinoblastoma (Rb) and p16 gene (29,40,
41). In large cell neuroendocrine lung cancer was observed the facilitation of p16 hypermethylation
in 48% of cases, compared to 33 % of cases of large cell lung cancers. This has
not been observed in small cell lung cancer. This hypermethylation facilitation
would be the cause of losing the p16 gene in both large cell lung cancer and in
neuroendocrine large cell lung cancer (25)
In neuroendocrine large cell lung
cancer was seen a intense coloration of CyclinD1 in 25% of cases (42).
The Study of
Genes
In neuroendocrine large cell lung cancer has been observed a MEN-1
mutation but none in small cell cancer. (43) This is important because in 67%
of cases of carcinoid tumors there is an inactivation of the MEN-1, making the
difference between carcinomas with high or low neuroendocrine degree
(43)
In 83 cases of lung cancer tumors with large neuroendocrine cells
have not been observed mutations for c-KIT,PDGFR alfa, PDGFRbeta or c-MET. But
in immunohistochemical terms
63% have been KIT positive
60% have been PDGFR alpha positive
82% have been PDGFR beta positive
47% have been c-MET positive (44). The only
prognostic factor was the expression of c-Met, which was correlated with the overall
survival. The Met-positive patients should be treated as patients with small
cell lung cancer and not after the treatment schemes of non- small cell lung
cancer (44)
The Kras mutations are rarely positive in
large cell neuroendocrine lung cancer, also the c-rafl mutations (45)
The Comparative Genomic Hybridization.
Through this
method have been compared with the large cell neuroendocrine lung cancer with
small cell lung cancer (46)
Common data:
losses in the areas 3p, 4q, 5q, 13q
Gains in the area 5p
Usually there
are aspects which show similarity between the two entities.
Instead, in case
of non-small cell lung cancer, the neuroendocrine large cell lung cancer is
similar to lung ADC.
Examples
Gains in the area 3p: 66% in small cell lung cancer
7,7% in the neuroendocrine
large cell lung cancer
Deletions in 16q area: 50% in small cell lung cancer
rare in
ADC and neuroendocrine large cell lung cancer
Deletions in 17p area: 75% in small cell lung cancer
Less
than 25% in the other forms (46)
After the work
of J.A.Eleazar and A.C.Borczuk(1) have been found
Deletions in 10q area : present in small cell lung cancer and in the
squamous form
Absent in neuroendocrine
large cell lung cancer
in ADC
Gains in the area 6p : present in ADC ,in squamous form and
in neuroendocrine large cell lung cancer
absent in small cell lung cancer
Loss of Heterozygosity (LOH)
LOH in the 3p area is frequent in neuroendocrine
large cell lung cancer and small cell lung cancer compared to carcinoids (47)
LOH in the 5p.21 area is frequent in
neuroendocrine large cell lung cancer and in small cell lung cancer and more
frequent compared to carcinoids (47)
LOH in the 5q area has been studied by SHIN
et al(39) and noticed frequencies ranging between 30% and 91%
A high frequency is observed in the 13q14 and
9p.21 both in small cell lung cancer and
in large cell neuroendocrine cancer.
All
neuroendocrine tumors have a high rate of LOH in the 11q area
The p53
abnormalities are frequent in large cell neuroendocrine lung cancer consisting
of LOH or mutations or both.
Within the
neuroendocrine tumors is noted:
LOH in TP53, point mutations in p53
Chromosomal
losses in
3p14.2 (FHIT),
3p21, 3p.22, 5q21, 9p21(p14) and 13q14.2(Retinoblastoma) is observed both in
small cell lung cancer and large cell neuroendocrine lung cancer and have a
reserved prognostic (47)
Large cell
neuroendocrine lung cancer shows chromosomal imbalances similar to those of
small cell lung cancer (,46,48)
Molecular
pathology. p53 and Rb pathways
Large cell
neuroendocrine cancer shows alterations similar to small cell lung cancer.
Thus:
- a high rate of p53 mutations (49,45,50,51)
- an over expression of Bcl-2 and under regulation
of Bax
-a high activity of telomerase
-the
p14ARF loss has the same frequency (40%) as in small cell cancer
- over
expression of Cyclin E is similar (50%) in both cancers and is simultaneously to
the Rb loss. The over expression of Cyclin E is correlated with the E2F1 over
regulation
- it is also seen a high level of MDM2 in
30% of cases of large cell neuroendocrine cancer and which is inversely related
to the loss of p14ARF(52)
- over expression of MDM2 and loss of Rb are
highly competitive in the neuro-endocrine cancers, especially in large cell
neuroendocrine cancer.
Apoptotic
Factors
Bcl-2 is an anti-apoptotic
protein. It is activated in large cell neuroendocrine lung cancer and small
cell lung cancer. The Bcl2/Bax default ratio is over unitary (36)
FAS and FAS LIGAND
FAS(CD95) is a target gene for the positive
transcription of p53 (53). Large cell neuroendocrine lung cancer has a strong
FAS under regulation, and half of the cases do not have it. The FAS expression score
is very low compared to normal tissue.
The FAS ligand was found over regulated in
40% of cases. Has the same frequency as in small cell lung cancer. The FAS /
FASLIGAND ratio is decreased below 1, as well as Bax-Bcl2 ratio. This reflects
a under regulation of the apoptosis in large cell neuroendocrine mitochondrial
cancer (36)
Angiogenic
Factors
In large cell neuroendocrine
lung cancer it was observed:
-over-expression of
VEGF
-a loss (40%) of Semaphorin
-an increase in the expression of neuropilin -
1(NP1) and neuropilin-2(NP2) with 70% –respectively 90% compared to normal
epithelium.
In short, large
cell neuroendocrine lung cancer has the same pattern of moderate expression of
VEGF and neuropilins, like small cell lung cancer (`36)
The adhesion molecule of the complex E-Cadherin-beta-Catenin
The large cell
neuroendocrine lung cancer has lost the normal expression of this adhesion complex
(54,55). Thus 84% have the staining affected for E-cadherin and 73% have the staining
affected for beta-catenin.
No mutations of
this complex have been observed in large cell neuroendocrine cancer. The expression
patterns of E-cadherin and Beta-catenin are common in large cell neuroendocrine
cancer and in small cell lung cancer. These data show the role had by the
disorder of cell adhesion complex in the pathogenesis of tumors with high
neuroendocrine degree. The lack of adhesion molecules may suggest the
possibility of transition from the epithelial stage to mesenchymal one (56).
For example there is a correlation between the alteration degree of E-cadherin
complex and the presence of gannglionic metastases in stages III and IV of the disease
(54)
Limpho-epithelioma-like
carcinoma
In contrast to
other tumours in this category, this form is not related to smoking, but to the
Epstein-Barr virus infection in Asian populations (57, 58).
Histologically, the cell is large, with vesicular nuclei, many nucleoli, cell
edges not being distinct (clear), suggesting a syncytium. What is important for
diagnosis is the association of some lymphocytic infiltrates (lymphoplasmocytes)
around the tumour nests or mixed among the tumour cells. It is also seen an inflammatory
cell response both in primary and metastatic areas
Genetically
It has EGFR mutations. The mutations are
usually associated with non-smokers and adenocarcinoma, but this was not
observed in this form of tumour (59 )
Through in situ hybridization has been
detected the Epstein-Barr virus in all cases. On the other hand, large cell
cancer and adenocarcinoma do not show the Epstein - Barr virus ( 60
)
A feature of this form of tumour is the
infiltration with mononuclear cells and the monocyte-chemoatractant-1 protein
(CAM-1) was shown in 86 % of cases.
The MCP-1 determination through the PCR
method has shown its presence in all tumours. But only the lympho - epithelial
tumours were positive by in situ hybridization method. The other cases of non- lympho
- epithelial -like tumours were positive by in situ hybridization for non-neoplastic
stromal cells , showing that there is a difference between MPC -1 in large cell
neuroendocrine carcinoma and MPC-1 in carcinoma forms similar to limpho -
epithelioma compared to non limpho - epithelial forms.
Basaloid
Carcinoma
Another form of large cell carcinoma is
basaloid carcinoma (61). Histologically it has a nodular appearance with
necrosis similar to large cell neuroendocrine carcinoma. But it lacks the neuroendocrine
markers. It is also missing the squamous differentiation, which accounts for a
poor prognosis (62).
Immuno-histochemical markers.
It is frequently
positive for KL1 Cyto-keratines and for Cyto- keratin with large molecule (34BE
12). TTF-1 is negative and reactivity for neuroendocrine markers is rare (61,33)
Prognostic markers and molecular pathways.
A study on 48
basaloid carcinomas showed that 50% had p16losses and a third had immunoreactivity
for cyclinD1 (63)
In terms proteomic basaloid carcinoma is a
unique subgroup within large cell carcinoma (64)
This type of
tumor shows an inverse relation with Rb and p16 and a direct relationship with Rb
and CyclinD1.
The reserved prognosis is associated with the
combination Rb negative p16positive and Cyclin D1 positive in basaloid
carcinoma (63).
Large cell
carcinoma includes:
a) clear cell
carcinomas. They do not show a squamous or glandular differentiation and the cells
have an accumulation of glycogen
b) large cell
carcinoma with rabdoid phenotype. It has
large eosinophilic inclusions. This form is
positive for vimentin and often for
pan-Cytokeratin and membrane antigen (65,66,67)
They stained
positively for Cyto-keratin 7 and neuroendocrine markers (65,66)
No
immunoreactivity was observed for TTF-1 (66)
The Main Changes
LARGE CELL CARCINOMA
It is a form of poorly differentiated cancer. The origin cell is not known.
Large cell carcinoma has ultra-structural appearance and histochemical phenotypes similar to lung adenocarcinoma
In large cell carcinoma prevail the cell cycle genes, DNA replication and transcription factors. The observed genes are the same as the genes during embryonic period, namely the during the pseudo-glandular and canalicular development period compared to lung adenocarcinoma where are prevalent the genes during embryonic period when terminal bag and alveolar stage develop.
In large cell carcinoma dominate the genes associated with proliferation while in adenocarcinoma dominate genes associated with differentiation.
The Main Molecular Changes
It is shown a large percentage of cyto – keratin 7
50 % of small cell carcinomas have immuno - reactivity for the TTF -1 gene
30% of large cell carcinomas have positivity for the cell markers of peripheral airways
They show p53 mutations, more frequent in smokers and those with poorly differentiated lesions.
Present the inactivating of p16 gene (71%) and RASSF1A tumour suppressor gene by hypermethylation
Kariotypic changes in large cell carcinoma are similar to those in non-small cell lung cancer.
Regarding the loss of heterozygosity in the areas 5q23, TP53, 13q14 and p12 are similar to lung adenocarcinoma
LARGE CELL NEUROENDOCRINE CARCINOMA
Comparative data with large cell carcinoma
SIMILARITIES It has a significant positivity for TTF-1 (35% -70%). It is not known whether this is due to a common origin or is a connection yet unknown of neuroendocrine differentiation
DIFFERENCES Cytokeratin7 is less frequent compared to large carcinoma
Has an increased expression of Bcl 2
Immunoreactivity for the p53 pathway is higher than in large-cell carcinoma (65% versus 35%)
Matrix metalloproteinase 9 has a high frequency and is responsible for invasion and metastasis
The p16 gene is hypermethylated in 48% of cases versus 28% in large cell cancer
Comparative data with small cell lung cancer
SIMILARITIES
Neuroendocrine cancers show chromosomal imbalances related to small cell lung cancer
Bcl 2-bax ratio is over uniform
The FHIT gene is inactivated by hypermethylation
LOH (loss of heterozygosity ) in the areas 3p, 5q, 9p21, 13q14 , and especially in the 11q area, LOH has a very high rate in all neuroendocrine cancers.
It slso present alterations similar to small cell lung cancer.
The rate of p53 gene mutations, over-expression of Bcl 2, the increased telomerase activity
Loss of the P14ARF gene, over expression of Cyclin 5
The high level of MDM2 in inverse relation to p14ARF gene. The MDM2 over expression is inversely correlated in neuroendocrine cancers
Bcl 2 ( antiapoptotic protein) is activated both in large cell neuroendocrine carcinoma and in small cell lung cancer
Shows the under regulation of FAS gene compared to normal epithelium. FAS ligand is over regulated in 40% of cases. The FAS - FASLIGAND ration is under uniform, similar in both forms of cancer
Similar to small cell lung cancer, has lost the normal expression of adhesion complex (E- cadherin - beta- catenin )
DIFFERENCES
There is the mutation of MEN-1 gene, which is absent in small cell cancer
Presents an inverse relationship between Rb gene and p16 gene
A high expression of cyclin D1
CARCINOMA LIMFOEPITELIOMULUI
Is associated with the Epstein-Barr virus infection showing this virus
Histologically has lympho-plasmocytes infiltrated around tumour nests
Has large cell, with vesicular nuclei, with imprecise cell edges.
Has infiltrated with mononuclear cells.
The monocyte-chemoattractant protein-1 is present in all cases.
Shows EGFR mutations
BASALOID CARCINOMA
Histologically resembles to large cell neuroendocrine carcinoma, but lacks neuroendocrine markers
It is positively present for KL1 cytokeratins and cytokine with high molecular weight (34BE-12)
Is negative for TTF-1
Have losses of the p16 gene (50%)
Has immuno-reactivity for Cyclin D1
In proteomic terms it is obviously a subgroup of the large cell lung cancer
CLEAR CELL CARCINOMA
Shows intra cellular accumulation of glycogen
Does not have squamous or glandular differentiation
LARGE CELL CARCINOMA WITH RHABDOID PHENOTYPE
Eosinophilic inclusions are present.
Is positive for the Vimentin protein
Is positively correlated to Cytokin7 and neuroendocrine markers
It does not have immuno-reactivity for TTF-1.
In the end I render the
pertinent conclusions of
J.A.Elazar and A.C. Borczuk(1)
Large cell carcinoma is a distinct group in
the group of non-small cell lung cancer. It presents immuno-histochemical, cytogenetic,
mutational (KRAS ) data, as well as the gene expression profile which overlap
with lung adenocarcinoma. This similarity reflects a probably common cellular
origin.
It is possible that the progenitor cells have
the capacity to differentiate in multiple cell lines. Large cell carcinoma may
represent a maturation stop leading to mixed histologies, as tumors where the
molecular profile overlaps, ranging from undifferentiated large cell carcinomas
up to differentiated adenocarcinomas. In the case of large cell neuroendocrine
carcinoma there are similarities with small cell lung cancer, carcinomas with neuroendocrine
component. But in many other situations overlaps with non-small cell lung
cancer. It still remains to be investigated whether there is a common cell
between these two formations with neuroendocrine components . It remains,
however, the existence probability of an intermediate phenotype between small
cell lung cancer and non-small cell lung cancer.
GLOSSARY
Cytokeratin7
– a low molecular weight cytokeratin. It is found in epithelial cells, and
epithelial cancers
Surfactant protein A - protein which gives a
high immunity, favours phagocytosis by macrophages; intervenes in the
production of surfactant
CD56 neural cell adhesion molecule (cluster
of differentiation) is a glycoprotein of the immunoglobulin family. It is used
for recognition of tumours. Normally found in NK cells, activated T cells. Small
cell lung cancer is positive for CD56
B72.3 monoclonal antibody. It helps in the
diagnosis of adenocarcinoma.
CyclinD member of the family of cyclin-proteins
involved in cell cycle regulation and in cell cycle progression.
RASSF1A a tumour suppressor gene. Loss or alteration of this gene’s expression
is related to the pathogenesis of cancer. It induces the accumulation of
cyclinD1, and induces the cell cycle stopping.
FHIT(fragile hystidin triade) tumour suppressor gene
c.MET is a proto-oncogene, which encodes
the Hepatocyte growth factor receptor protein, which has a tyrosine kinase
activity. It is a sign of severe prognosis. stem
cancer cells express c-Met and become the cause of cancer resistance and
diffusion.
Menin
is a protein encoded by the MEN-1gene. It is located in the long arm of
chromosome 11q13. Is associated with glandular tumours.
PDGFR(platelet derived growth factor
receptor) is a tyrosine-kinase receptor of the cell surface.
Tyrosine –protein-kinase KIT is a protein
encoded by the KIT gene. Is a cell surface marker.
c-RAFL is an oncogene
p14ARF is the product of CDKN2A. It is
involved in cell cycle regulation. Inhibits [MDM2, which favours p53, which in
turn promotes p21 activation. Loss of p14ARF through homozygous mutations in
the INK4A(CDKN2A) gene leads to increasing MDM2, loss of p53 function and cell controll.
Cyclin E is a member of the cyclins
family. It binds CDK2 to G1 phase necessary
for the transition from G1 phase to S phase
E2F1 is a transcription factor encoding the E2F1 gene. The E2F1 transcription
factors family plays a crucial role in the cell cycle and action of tumour-suppressor
proteins
MDM2(murine double minute2) is an
oncogene encoding the MDM2 protein which is an important negative regulator of
p53tumour-suppressor gene. Its level increases in some cancers.
FAS. In the molecular mechanism of inducing activation
of T cell death have been found the FAS molecules (CD95) and FAS ligand. Binding
of FAS and FASligand is a homeostatic control mechanism for maintaining the
number of T cells. FAS and FASligand form an apoptotic pathway.The FAS receptor
is a cellular receptor protein belonging to the TNF receptor family (CD95),
which induces apoptosis by attaching to Fasligand.
Semaphorin.
SEMA 3E.-plexin.D1. Modulates angiogenesis through a feed-back mechanism
via VEGF
Neuropilin is a receptor protein active
in neuron. They are transmembrane glycoproteins and co-receptor of semaphorin.
Also VEGF is another ligand for neuropilin. Neuropilin inhibits cell migration
and adhesion and increases chemo-sensitivity
Cyto keratin with high molecular weight is a monoclonal antibody that
recognizes keratins 1,5,10,16.Is a good marker
for myoepithelial cells.
PAN-Cytokeratina(KL1). It is
recommended for the detection of cyto-keratins. Cyto keratins play a role in
the differentiation and specialization of tissues and maintain the integrity of
epithelial cells. They are important markers for the characterization of
malignant tumours. For example cytokeratin 10 and 13 express very well the
subset of squamous form, while the of cyto-keratin18 is expressed in lung
adenocarcinoma.
VIMENTIN is a type III-filament protein
that is expressed in mesenchymal cells Vimentin is the major cyto-skeletal
component of the mesenchymal cells.
Vimentin is used
as a marker for cells derived from mesenchyme or for cells suffering the
epithelial-mesenchymal transition during development and metastasis
Cytokeratin
antibody(34betaE12) antibody with high molecular weight. Its increased
expression is noted in lung basal cells, in squamous lung cancer, basaloid cancer,
in mesothelioma. It does not stain Clara cells and pneumocyte II and the
reaction is negative in neuroendocrine tumours. Is not related to
adenocarcinoma.
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