H*****e
发帖数: 120 | 1 Wow, on the top list!
Well, I never expect to be on the top list. This reason is that I am not
here very often. Also apologize to those are discussing about the topic and
expect me to give my opinion.
I believe that the previous title regarding to someone retract her paper is
misleading. So it is necessary to clear some issue and have an opportunity
to draw more discussion. Now back to the stem cell issue not the Amy or
Carla although name may be mentioned but please ignore my own personal
opinion on both of them. Also I like to restrict my view on lung and lung
cancer in case that I forget type lung.
1. Lung stem cell?
Is there lung stem cell? Unlike many other tissues, the lung tissue
turnover is very very slow. So once, it has been almost accepted that there
is no stem cells in lung. This is changed until everyone accepted the lung
epithelial injury model: chemical induced lung injury. Specific layer of
epithelial can be “removed” by carcinogen although the mechanism is not
completely understood. So the idea is that there are unclear stem cells: 1)
to join Clara cells recovery the airway and bronchial epithelium; and 2) to
become type II cells and then type I cells to repair alveolar.
Now where is the stem cell population? Carla Kim’s Cell paper found BASCs
and a almost perfect situation to solve it. This is not only the perfect
new type of cells but also perfect location in term of lung anatomy. Her
other works even pointed to the direction that lung cancer is from BASCs.
However, it then became to be too good? There are people arguing the wrong
technology or wrong marker in Carla’s work. There are people who
identified new stem cells with new identity. Then Carla argued back that
others used wrong antibody. (Please forgive me ignore the reference because
it is very easy to find on pubmed!)
Then, partial answer is from Hogan’s work using the transgenic mouse to
track the lineage. The conclusion is that Clara cells in airway and
Bronchial epithelium is self renew population. So Clara cells can to self
repair! Can we call Clara cells stem cells? Or it is just because there
are too many! And beyond our imagine about the “very small number of cells
” in lung?
I said “partial” above. The reason is the unanswered question regarding
to type II cells? Way back to decades ago, text book said type II, like
Clara cells, can repopulate itself. In Carla’s earlier year seminar, she
gave very strong statement that there was no evidence about type II
repopulation. I personally hate any strong statement like Amy’s no
transdifferentiation. However, this is no clear answer!
2. Lung cancer stem cells?
Without mentioning how people using the stem cell marker to search cancer
stem cells, this concept may not be right in lung cancer. Narrow down to
adenocarcinoma since Kras and VEGF models’ major/only consequence. Earlier
work used Tag can reach the same tumor by CCSP or SPC promoter, concluding
that tumor could be from both type II and Clara cells. This seems confirmed
by carcinogen induced AJ mouse tumor (I always wonder why this strain get
tumor but not the common Black strain?) and by EM too. Then people found
that CCSP does not express well in tumor; so a theory is that Clara cells
no longer express CCSP when it become tumor and somehow the gene is shut
down. Then why the transgene remains on? By selection?
So if there is lung cancer stem cell, it should be more than one type, at
least one for typeII tumor and one for Clara tumor. As matter of fact, I
suspect it for long time when I was a strong believer of cancer stem cell.
This seems being answered by Carla’s Cell Stem Cell paper recently that
Kras and EGFR tumor stem cells have different potency and identity (?).
Then are they all from BASCs? Or other common population?
I had done experiment to express Kras or EGFR in either typeII or Clara
cells but found that they all form tumors. An experiment that I designed to
get the answer but generate more question!
3. What is lung cancer origin?
In the above discussion, I more or less touched this issue. By microarray,
there are 6-7 types of NSCLC and, among them, there are at least 3-4
different adenocarcinoma. This is human case. Is mouse same of different?
For many years, I try not to touch this issue because I know I only care
about result and publication. Now this becomes concept issue. I have been
asked for it. I have no answer. But to Kras model, I like to say this only
represent one type of adenocarcinoma. Then what is the origin of Kras lung
cancer in mouse? By histology, I see most tumors in alveolar. So I vote
for typeII cells. Then question is what will happen if someone see a tumor
in bronchial.
Why this is a concern? I care about this issue from my concern about which
type of cells may act like stem cells then cancer stem cells. But my friend
in carcinogen field told me that this is very important. Smoke carcinogen
can only be metabolized by P450 Cyp2a13, which only is expressed in airway
and bronchial epithelium not alveolar type II cells. The injury is seen in
bronchial. But DNA adduct (I know little about this term) was seen in both
type of cells? To them, they like to know which cell is the targeted cells
that generate mutation. Then I told him both cells can form tumor by
arguing that only 20% NSLC is related to smoke. Practically, I then start
to wonder if I can identify the origin of certain lung cancer I may choose
the right cells to study the initiation stage. Now which cells to choose,
typeII or Clara? So I selected BASCs for some time and realized that these
is no such thing. Then what is my next cell?
4. Stem cell population in cell lines?
I read some comments about the cell lines. It recalled me a manuscript that
I had reviewed. This manuscript, like some of them out there, used the
markers (SCA, CD133, CD166…) to stain MCF7 and SW480 cells for cancer stem
cells. I rejected it because I know that the chromosome number in a plate
of cells vary between 1N to 4N and their identities may vary by some markers
. However, not every reviewer agrees or knows this fact. One has not
problem to find this type of work. Indeed, there is a paper which did all
“stem cell marker” staining on the NCI cells and reported all the
percentage for each stem cell markers. It turns out that some cells has >90
% stem cells and some has <1%. I believe that this is great paper that
gives people the fact and they can choose what to think. To me, a single
cell of cell line can form not only the colony but also tumor without too
much problems and by concept cell line is stem cell. Then, there is no stem
cell because they are all stem cells now. Also different cell lines from
the same cancer can have different identities. Then my guess is that each
individual tumor has its own specific stem cell. Why we work on stem cells?
5. What I am going to do?
Now back to earth, I hate this concept like many senior scientists in the
field but I have to follow it in case that … The other reason that I did
not stop working on “lung cancer stem cells” by using different markers is
the application of specific marker producing a defined population of cancer
cells, which may be more “pure” for other experiment such as microarray
etc. At least, the experiment can be reproduced. Otherwise, using the
primary tumor even Kras mouse, I found the result varies from time to time.
In case that I used the one right marker that people call it stem cell
marker someday, I …
Again, I am not here very often. If there is anything wrong, this is
restricted to BBS discussion or forgive me base on how much I typed tonight.
If you need my help, I do not want to mislead you as I already did to
myself as described above. If you like to have more discussion, I am open
for it but again I am not here very often. Also please no personal attack.
I am not feeling well by mentioning Amy and Clara since we know each other
well. | h********n
发帖数: 4079 | 2 great post.
To me, the cellular origin of a specific lung cancer is one of the most
important questions.
When I have time I will discuss more. | r***e
发帖数: 2539 | 3 非常不错的总结！
我也比较支持KRas induced adenocarcinoma是从type2 cell出来的，从histology很容
易看到。
另外ccsp promoter的specificity比较难说，至少ccsp-rtTA的表达在type2 cell。我当
时看某些文献也糊涂了半天。见G&D 2001 15:3249
and
is
opportunity
【在 H*****e 的大作中提到】
: Wow, on the top list!
: Well, I never expect to be on the top list. This reason is that I am not
: here very often. Also apologize to those are discussing about the topic and
: expect me to give my opinion.
: I believe that the previous title regarding to someone retract her paper is
: misleading. So it is necessary to clear some issue and have an opportunity
: to draw more discussion. Now back to the stem cell issue not the Amy or
: Carla although name may be mentioned but please ignore my own personal
: opinion on both of them. Also I like to restrict my view on lung and lung
: cancer in case that I forget type lung.
| H*****e
发帖数: 120 | | w**********9
发帖数: 242 | 5 my mistake. No bother
【在 H*****e 的大作中提到】
: No evidence!
:
: all
| h********n
发帖数: 4079 | 6 if AT2 cell is stem cell, there will be too many stem cells.
AT2 cell should be differentiated cell.
all
【在 w**********9 的大作中提到】
: my mistake. No bother
| H*****e
发帖数: 120 | 7 I was asked a question whether it is meaningful to search the cancer origin
of lung cancer in kras model.
Actually, I found that I have no answer after taking more thought about it
and why I am doing it. So I open it for more discussion:
The promoter driving Kras is SP-C, active in both clara and type II cells.
I get myself into it because of Carla's finding on the stem cells. Since I
could not find the evidence to support stem cells, I then asked myself which
cell can form cancer. Obviously, both can based on literature. So I am
really lost on this project. As for Kras, it is then probably not important
since it may only represents for one out 6-7 human lung adenocarcinoma.
Then am I on it because I am on it?
The only reason that I guess that I like to continue is also from Carla's
work on the Kras and EGFR stem cells, which suggests that different gene
mutation may have different impacts on different cells. |
|
