I think the best way for tracing the potential of metastasis in cancer cells especially those cause solid tumors, is to evaluate the level of matrix metallaprotinasease (MMPs) enzymes which are non specific for tumor cells but if elevated level of them in tumor microenvironmentis is observed it can indirectly imply to the high risk of metastasis. This issue recently is being used for monitoring some of the cancer therapeutic strategy. For instance high level of MMP9 or MMP2 in prostate cancer patients can be related to the aggressive disease. Following link would confirm this claim:

http://www.ncbi.nlm.nih.gov/pubmed/21391788

There is some evidence that hyaluronan producing enzyme,HAS, is over expressed in metastatic cancer cells. This will be related to the surrounding matrix but originates in the cells themselves.

@ Heiko Käfferlein: Does your statement reflect your opinion or can you back up your statement with publications?

A MedLine reference: 23743930 is about Bio-Banking as an approach to study the molecular profile of mts, published by Zuanel Diaz et al in 'Modern Pathology'

Metastatic cancer has the same name and same type of cancer cells as the original cancer. So the cell type in the metastasis must be the same as in the primary tumor, which must be in a different part of the body as the definite proof of a metastasis is a biopsy showing the primary cell type. I think this commonly agreed upon (Note I am not a MD). I doubt whether a second tumor in the same tissue type is considered a metastasis and how in this case the distinction between the primary and secondary tumor is made.

@ Josef Käs: there are plenty of clinical evidence of how well described by Heiko. For example, renal cell carcinoma (clear cell carcinoma, etc..), even with massive infiltration of the renal vein (which in many cases I prefer to call prolapse into the renal vein), and large neoplastic thrombus in the vena cava, it is not always associated with metastatic disease although many neoplastic cells reach the lungs. Even in the case of one or a few metastases does not mean it is a systemic metastatic disease and this justifies a very aggressive surgical therapy in individual metastases. Metastases may recur, in various locations, many years later. There are also examples of benign lesions with lymph node localization (not always a sign of multicentric) as in typical and atypical nevi etc.

Diagnóstico de metástasis: (Metastasis diagnosis):

-Se suele realizar una analítica general en la que pueden aparecer una anemia o el calcio elevado.

-Otra analítica son los marcadores tumorales como el CA-125, PSA, CEA o ß2-microglobulina.

-Gammagrafía ósea, que mediante un marcador radioactivo aparecen las células de metástasis marcadas, ya que tienen más actividad y fija este marcador.

-La Resonancia Magnética y el TAC o Escaner, que están indicados en ciertos casos.

-La biopsia de lesiones sospechosas.

-La Tomografía por Emisión de Positrones (PET en inglés) es una técnica de diagnóstico no invasiva que permite realizar imágenes que muestran el metabolismo y el funcionamiento de tejidos y órganos, es muy sofisticada y solo indicada en algunos casos por índice de rentabilidad.

This:

-Otra analítica son los marcadores tumorales como el CA-125, PSA, CEA o ß2-microglobulina.

-Another analytical are tumor markers such as CA-125, PSA, CEA and beta2-microglobulin.

http://www.tuotromedico.com/temas/metastasis.htm

Dear Josef,

Carcinoembryonic Antigen, CEA:

CEA levels can be used as indicators of treatment success. The normal values range from 0.0 to 2.5 ng/ml of serum (from blood), in non-smokers, a greater amount than that may be suggestive of cancer.

*Levels above 20 ng/ml before treatment are associated with cancer which has already metastasized*. Benign conditions do not usually cause a CEA increase over 10 ng/ml.

*Seems to work for metastasic colon cancer*.

Source (among others): ProSpec (Protein-Specialists)

Regards

Frank

Hi, Josef

I think there're two theories concerning the origin of metastatic cancer cells.

One is the primary tumor contain specific cancer cells that can leave the tumor and cause metastasis (cancer stem cells) as you mentioned, and another is the cancer cells gain the metastatic ability in the tumor microenvironment (hypoxia, cytokines from inflammatory cells and ROS etc. = genetically or epigenetically changed).

If you want to check the primary tumors, CD133, CD44 could be good markers for cancer stem cells, and you could find good markers for cancer stem cells below.

http://www.rndsystems.com/molecule_group.aspx?g=1763&r=0

I hope this would be helpful for you. Good luck! ^_^)b

An interesting study, opening a very promising approach

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0076438

This of course depend on the origin of the cancer. We have researched this extensively and RKIP, Raf kinase inhibitory protein seems to be lost from almost all types of metastatic cancers. Marker by absencia!!

Ramaswamy and colleagues reported on a metastasis signature (http://www.nature.com/ng/journal/v33/n1/full/ng1060.html) that contains many players of the microenvironment (http://link.springer.com/article/10.1007%2Fs10555-007-9111-x). The microenvironment influences the cells' ability to leave the primary tumor as well as their ability to survive in the target tissue and finally to grow there. Between the latter two there may lie many years.

There are no specific marker because there is no "ONE" cancer. To add complexity, every patient will experience different sites and rates of metastasis. However, there are patterns to be observed even though not always true. This is one of the major reason why there are so few reliable cancer biomarkers. One example is Prostate Specific Antigen (PSA): often elevated in patient with prostate cancer and more elevated in metastatic prostate cancer, some patients lack PSA or non-cancer patients express high PSA. There is no easy way to identify metastatic cancer cells because they constantly chaneg during cancer progression.

Dear Josef, it depends on what kind of cancer you're analyzing. In colorectal cancer CD26 could be a good marker of metastatic cancer cells (http://www.sciencedirect.com/science/article/pii/S1934590910001566), moreover it seems that in many cancers metastatization process proceeds through the transformation of the epithelial cancer cells in mesenchymal-like cancer cells (epithelial-mesenchymal transition). During the EMT cells acquire specific mesenchymal characteristics (for example N-cadherin, vimentin, CD90 expression) and lost some epithelial features (for example EpCAM expression) (http://www.jci.org/articles/view/39104/pdf/render, http://www.sciencedirect.com/science/article/pii/S0092867409014196,http://www.nature.com/nrc/journal/v9/n4/abs/nrc2620.html).

Hope this could be useful!

Bests

Marica

Despite the absence of specific marker for metastasis, I think detection of circulating tumour cell in the blood may provide an important evidence for metastasis in condition that those cells may represent a sub-clone of the primary tumour.

There are some biomarkers that are tightly coupled with metastasis and death of patients, eg. osteopontin in breast cancer. See http://cancerres.aacrjournals.org/content/62/12/3417.short

for instance

I think you can look the different kind of microtubules and its antigen-antibody reaction.

If exist differences in microtubules between normal cell (differentiated cell), and cancer cell (non differentiated).

Regards.

Yes, of course. The markers are available to identify the metastatic tumor cells. The explanatory question by you : "Does a primary ..." The metastatic clone / metastatic signature concept will well explain you on this aspect. Please follow the websource on the suggested concept. The explanatory question: 'Or are these changes...' The metastatic event of the tumor cell is an hallmark of the neoplastic cell. Hence, the changes are triggered in the neoplastic cell and also the microenvironment provides the additional support. The microenvironment changes provides the tumor cell to be motile and gives the way to relocate the altered / mutant / neoplastic cells.

As mentioned in all the above posts this will depend on the Primary Tumor. The tumor microenvironment to a larger extent also dictates the metastatic signature hence if you know the nature/secondary site of metastasis then you could narrow down on a marker. Metastatic signature is partly decided at the primary tumor site and then the metastatic microenvironment also dictates changes in the signature. If you would like to explore/track these cells and understand the changes then for tracking I would not rely on a marker but on a panel to ensure effective tracking of these cells.

Voltage-gated sodium channels are related to invasion in diferent kind of cancers. In several papers it has been shown that the functional expression of these proteins are enough to increase the invasive and metastatic potential of cancer cells:

Overexpression of NaV 1.6 channels is associated with the invasion capacity of human cervical cancer: Int J Cancer. 2012 May 1;130(9):2013-23.

Voltage-gated sodium channel activity promotes prostate cancer metastasis in vivo: Cancer Lett. 2012 Oct 1;323(1):58-61.

Therapeutic potential for phenytoin: targeting Na(v)1.5 sodium channels to reduce migration and invasion in metastatic breast cancer: Breast Cancer Res Treat. 2012 Jul;134(2):603-15.

To date specific cell markers to identify metastatic cancer cells do not exist. However it has been demonstrated that loss of cell adhesion molecules (for example Cadherins) promotes metastatic ability. Therefore in a tumor the group of cells not expressing these markers represents the population prone to metastatize.

Yes, there are. I think the metastatic markers for cancer are almost close to markers associated with stem cells which differentiate to tumor cells.

Intratumoral and intertumoral heterogeneity results in numerous markers of metastasis. Depending on the tumor type and model, any of a hundred different surrogates can correlate with metastasis. The "real" question is what marker will identify all metastatic cells. Indeed, due to biologic redundancy it is likely that no one marker will identify “all” metastatic cells. As an example the first IVD that was FDA approved for breast cancer, which uses fresh frozen breast cancer tissue samples to assess a breast cancer patient’s risk for distant metastasis (MammaPrint) used an assessment of mRNA expression for 70 genes.

I agree to Gianluca Marucci's opion:no specific cell markers to identify metastatic cancer cells now.

A fascinating point is that several cancers acquire genes and produce proteins that regular cells might not produce. Many of these genes have been identified in embryonic development and disappear within days or weeks post differentiation. Cancer cells seem to re-express these genes during carcinogenesis (there must be a growth advantage...). There is an interesting (understudied) link between development and cancer. Maybe specific metastasis markers will be discovered this way. Something to think about...

The question is what would be the perfect protocol design to discover early metastasis indicators.

Pretty interesting article in Cancer Stem Cell regarding miRNAs, specifically 708 which minimally is down regulated in metastatic cells. Not quite a marker, but a good clue. Not sure how many different metastatic cells this holds true for but a very good paper nonetheless.

Suppression of miRNA-708

by Polycomb Group Promotes Metastases

by Calcium-Induced Cell Migration

Cancer Cell 23, 63–76, January 14, 2013 ª2013

This is difficult , but you can look less genes of differentiation. But I don't know how, where... This cells are less first.

molecular profiles of cancerous cells, or the gene expression in cancerous cells, could potentially identify the metastatic capabilities of these cells. As for the specific markers, it would depend the classification of the cancer.

The cells that undergo epithelial-mesenchimal transition may be able to go around and invade/metastasize. And these cells are likely to be the "cancer stem cells". However, it is still debatable issue! It is also believed that these cells and microenvironment feed eachother via cytokines (e.g. IL-6) etc...

I depends on the type of the cancer, there are many immunostains will help if you have tiisue

This sounds interesting!

Am J Physiol Cell Physiol. 2013 Oct 16. [Epub ahead of print]

Theme: Physical Biology in Cancer. 2. The physical biology of circulating tumor

cells.

Phillips KG, Kuhn P, McCarty OJ.

Oregon Health & Science University.

The identification, isolation, and characterization of circulating tumor cells

(CTCs) promises to enhance our understanding of the evolution of cancer in

humans. CTCs provide a window into the hematogenous, or "fluid phase" of cancer,

underlying the metastatic transition in which a locally contained tumor spreads

to other locations in the body through the bloodstream. With the development of

sensitive and specific CTC identification and isolation methodologies, the role

of CTCs in clinical diagnostics, disease surveillance, and the physical basis of

metastasis continues to be established. This review focuses on the quantification

of the basic biophysical properties of CTCs and the use of these metrics to

understand the hematogenous dissemination of these enigmatic cells.

PMID: 24133063 [PubMed - as supplied by publisher]

Look this:

http://www.conciencia-animal.cl/paginas/temas/temas.php?d=1077

This looks interesting

Science. 2013 Dec 6;342(6163):1243259. doi: 10.1126/science.1243259.

Single-cell metabolomics: analytical and biological perspectives.

Zenobi R.

Department of Chemistry and Applied Biosciences, ETH Zürich, CH-8093 Zürich,

Switzerland.

There is currently much interest in broad molecular profiling of single cells; a

cell's metabolome-its full complement of small-molecule metabolites-is a direct

indicator of phenotypic diversity of single cells and a nearly immediate readout

of how cells react to environmental influences. However, the metabolome is very

difficult to measure at the single-cell level because of rapid metabolic

dynamics, the structural diversity of the molecules, and the inability to amplify

or tag small-molecule metabolites. Measurement techniques including mass

spectrometry, capillary electrophoresis, and, to a lesser extent, optical

spectroscopy and fluorescence detection have led to impressive advances in

single-cell metabolomics. Even though none of these methodologies can currently

measure the metabolome of a single cell completely, rapidly, and

nondestructively, progress has been sufficient such that the field is witnessing

a shift from feasibility studies to investigations that yield new biological

insight. Particularly interesting fields of application are cancer biology, stem

cell research, and monitoring of xenobiotics and drugs in tissue sections at the

single-cell level.

PMID: 24311695 [PubMed - in process]

There may be specific cell markers to identify metastatic cancer cells and these would be important to identify. Notably, circulating tumor cells have an altered cytoskeleton and microtentacles that protect from deformation caused by shear stress. Interestingly, both carcinogenic and non carcinogenic circulating breast cells have microtentacles but those in tumorigenic cells are extra long and motile compared to those in non-tumorigenic cells (Cancer Res. 68, 5678-88, 2008; Cancer Res. 70, 8127-37, 2010). Microtentacles, which are formed by microtubules and also may contain intermediate filaments, are required for efficient attachment and act in the metastatic spread of cancer. Interestingly the common chemotherapeutic paclitaxel, which acts by stabilizing microtubules, strengthens the microtentacles resulting in increased attachment of circulating tumor cells to secondary sites (Breast Cancer Res Treat. 121, 65-78 (2010) so this type of one highly successful therapy for primary tumors may set the stage for a greatly increased risk of metastasis. The observation that ~90% of all cancer deaths are caused by metastatic spread of the primary tumor underscores the importance of this question: the need to understand circulating tumor cells and how they find favorable attachment sites and what their mechanisms of reattachment may be.

I read with great interest about the microtentacles written by John in the circulating cancer cells. Do you know if these characteristics were also evaluated in the in situ carcinomas (in particular high-grade) ? In in situ carcinomas, there is sometimes a loss of cohesiveness and the single cell has little or nothing of the normal counterpart, but when the cells infiltrate the stroma they take on characters that resemble the normal cell due to epithelial-stromal interaction . In fact, this is particularly evident in "simple" situations, such as in cervical squamous cacinoma and in adenocarcinoma of the large intestine (in these cases, histology and is relatively homogeneous) . In breast these aspects seem to me more complicated for many histotypes that are present and also because with the same definition probably we indicate different diseases (eg high grade intraductal carcinoma etc.).

In other words, if you believe that what has been described by John in circulating cells could provide information on the mechanisms that drive the infiltration and conversely to add something about the meaning of microtentacles .

Urine and bladder washing cytology may provide a lot of material in a simple way and without interfering significantly with normal diagnostic and therapeutic processes.

http://www.pathologyoutlines.com/topic/bladdercis.html

In correlation to John Trainer and Maurizio Pea: there is less than 1 cell in a million that will "successfully" metastasize. Would that cell do so in a microtentacle-dependent manner? In accordance with your interesting comments, what is different about these cells that have microtentacles as compared as other cells in the tumor and its microenvironment? Does the type of tissue and type of tumor affect microtentacles? Are metastases also composed of these microtentacle cells? If it is a required mechanism for aggressiveness, we must isolate them by laser dissection and look at what makes them different.

Paclitaxel has started making me fear of it. It was shown that it also makes the enrichment of CD133 positive cells (cancer stem cells?) both in vitro and in vivo. So, it may increase the relative number of cancer stem cells and their reattachment as well???.

To Antoine, Maurizio and John. Excuse me if I'm naive but the cells developing those micro tentacles, in high grade in situ lesions are perhaps just invasive but not metastatic? Mine is a question from ignorance. Really. I do not know for certain but perhaps tumor cells with invasive capacity are not necessarily good enough to migrate through blood and lymphatic vessels and successfully establish themselves in a remote position. What if they have to develope even more characteristics like for example expressing those genes allowing it to avoid apoptosis induced by natural killers or that kind of cells? I mean the cells present in blood stream may well induce them death? What if they have to be able to reach extremely different tissues by expressing new adhesins? My question above was: How do we develop a protocol to discover early metastasis markers? Availability to tell what patients are in stages where metastasis is already being present, would save more lives than the ones are saved right now. Of course I'm looking forward to hear your opinions. Please. And thank you for your comments above. I'm enjoying myself with your opinions really!

Dear Paula, when we indicate that a cancer is "in situ" we mean that there is no evidence of stromal invasion, nor even of distant spread. In addition there are differences in the phenotype that are not intuitive (carcinomas in situ cell "uglier" than those infiltrating). I do not know the answer to your other observations.

To Paula. Your point is a valid point. Whatever these cells do, some, probably a very low amount, reach distant organs to form metastases. Maybe the cancer "itself" does not know what is the best way to survive. Having fast proliferating cells brings a growth advantage. The point here (and your question) is that are there markers for early metastasis? Cancer needs to adapt and transform continuously. From the point of view of cancer, it is better to NOT have specific markers or maybe to have many that constantly can be "replaced." Our immune cells are efficient at recognizing cancer cells but still get "tricked". Cancer is a very low efficient model but still is able to outcompete our "normal" cells. It will do whatever it needs to do to reach its means. Specific markers??? to my opinion, no!

Stem Cells. 2012 Feb;30(2):292-303. doi: 10.1002/stem.791.

Epithelial and mesenchymal subpopulations within normal basal breast cell lines

exhibit distinct stem cell/progenitor properties.

Sarrio D, Franklin CK, Mackay A, Reis-Filho JS, Isacke CM.

Author information:

Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research,

London, United Kingdom. [email protected]

It has been proposed that epithelial-mesenchymal transition (EMT) in mammary

epithelial cells and breast cancer cells generates stem cell features, and that

the presence of EMT characteristics in claudin-low breast tumors reveals their

origin in basal stem cells. It remains to be determined, however, whether EMT is

an inherent property of normal basal stem cells, and if the presence of a

mesenchymal-like phenotype is required for the maintenance of all their stem cell

properties. We used nontumorigenic basal cell lines as models of normal stem

cells/progenitors and demonstrate that these cell lines contain an epithelial

subpopulation ("EpCAM+," epithelial cell adhesion molecule positive

[EpCAM(pos)]/CD49f(high)) that spontaneously generates mesenchymal-like cells

("Fibros," EpCAM(neg)/CD49f(med/low)) through EMT. Importantly, stem

cell/progenitor properties such as regenerative potential, high aldehyde

dehydrogenase 1 activity, and formation of three-dimensional acini-like

structures predominantly reside within EpCAM+ cells, while Fibros exhibit

invasive behavior and mammosphere-forming ability. A gene expression profiling

meta-analysis established that EpCAM+ cells show a luminal progenitor-like

expression pattern, while Fibros most closely resemble stromal fibroblasts but

not stem cells. Moreover, Fibros exhibit partial myoepithelial traits and strong

similarities with claudin-low breast cancer cells. Finally, we demonstrate that

Slug and Zeb1 EMT-inducers control the progenitor and mesenchymal-like phenotype

in EpCAM+ cells and Fibros, respectively, by inhibiting luminal differentiation.

In conclusion, nontumorigenic basal cell lines have intrinsic capacity for EMT,

but a mesenchymal-like phenotype does not correlate with the acquisition of

global stem cell/progenitor features. Based on our findings, we propose that EMT

in normal basal cells and claudin-low breast cancers reflects aberrant/incomplete

myoepithelial differentiation.

Copyright © 2011 AlphaMed Press.

PMID: 22102611 [PubMed - indexed for MEDLINE]

There are no universal marker for MCC. When we do pathological diagnosis, we use several markers to identify primary organ of MCC.

To Paula and Antoine

A currently running hypothesis on the invasion-metastasis cascade explains the successful dissemination of a cancer cell from the primary site to a distant macrometastatic lesion by the phenotypical plasticity of the cancer cell. In fact, the different barriers a cancer cell is confronted with during the journey to a distant organ would require a high degree of plasticity to withstand the diverse hurdles that are characteristic for each phase in the metastatic process:

1. local tissue invasion: motility, basement membrane degradation, single cell invasion (EMT or amoeboid), collective migration,...

2. Intravasation: transendothelial migration, interaction with pericytes

3. CTCs: shear stress, anoikis resistance

4. Extravasation

5. Entry into foreign organ tissue: hostile environments, settlement, proliferation, dormancy....

For example, EMT would benefit invasive cells in the first phase, yet it might be disadvantageous for cells to continue exhibiting EMT in the circulation, so they might need to change their phenotype again to a robust, non-proliferating, stem-like phenotype to survive the circulation. Metastatic lesions often display similar degrees of differentiation as the primary tumour, so after the acquisition of a proliferative phenotype to colonize the distant organ, cancer cells may undergo a MET program in order to re-adopt a more differentiated state. In this model of cellular plasticity, the concept of migrating cancer stem cells has been included to explain for the different states and their interactions.

More on this can be found in a recent overview by several metastasis researchers: Brabletz T et al, Nat Med 2013.

Dear Ridha, thank you very much for your thoughtful reply. I have studied all those aspects of development of metastasis from the biology of tumors point of view. Thank you for pointing out the review. I wish you a wonderful productive happy new year.

Short answer is NO. Most of what has been written here to answer this question provides the same answer. Solid tumors are very complex deranged tissue imbedded in normal tissue. These are very dynamic structures that are in flux and constantly changing in time. All cell types (epithelial, fibrobastic, immuno (lymphocytes), endothelial, adopose, etc.) within the tumor mass are somewhat or very much altered from their corresponding normal counterparts with respect to their interactions, metabolic processes, metabolic rates, fuel preferences, proliferation rates, etc. The plasticity (genomic/genetic instability) of cancer lesions continuously gives rise to cells with enhanced survivability under adverse conditions. But this is not a constant of a single population of cells nor do these potentials remain constant over the growth of the tumor and there will be a range or spectrum of these changes throughout the tumor. So a variety of cell markers "come-n-go" (so to speak). Long years of work in thousands of labs and clinics has yet to provide a single unique metastatic marker. There may be metastatic phenotypes but even this is questionable as dormant cancer cells (phenotypically similar to primary site cancer cells) lodged in potentially metastatic sights might remain there without change (sometimes for years) until conditions ignite their regrowth. A panel of metastatic markers (as already suggested here) may be drawn upon in a statistically relevant context, i.e., determined from large scale human clinical trials, to aid in diagnosis and prognosis and treatment regime choice.

Nature.com has specific related content:

Nature Conferences

Sponsored Subject Page: Cell Signaling

Sponsored Subject Page: Cell Migration

The content table for each issue is send at no cost for registered users to their e-amil address. Hope it's useful. Salut

The poor prognosis and a low survival rate of oral carcinoma is related to the risk of cervical metastasis. Metastasis of oral cancer is a complex process involving detachment of cells from the tumor tissue, regulation of cell motility and invasion, proliferation and evasion through the lymphatic system (the incidence of occult neck metastases in stage I/II disease to be as high as 42%). This process is due to reduced intercellular adhesion of tumor cells as they progress to malignancy because of loss of E-cadherin; they thereby begin to express proteins such as mesenchymal vimentin and N-cadherin, promoting cell elongation and interfering with cell polarity. This morphological transition, called epithelial-mesenchymal transition (EMT) leads to molecular alterations interfering with the behavior of these cells. While it is widely accepted that more advanced oral tumors be treated with elective neck dissection, management of stage I disease remains controversial. In the absence of clinical neck disease, stage I oral cancer is often treated with primary tumor resection and clinical follow-up of the neck.

Some groups are working on early cancer diagnosis biomarkers using systems biology approach (integrating genome wide association of integrating genomics data with transcriptomics, proteomics, metabolomics and PTMs). Studies have also been going on to understand tumor microenvironment but, some solid acceptable data is yet to emerge. Tumor may be bening or metastatic, tumor just does'nt contain only cancer cells they contain other cells too. The cancer cells produce some metabolites/ proteins that recruit surrounding cells to produce chemokines to support cancer growth, maintenence and malignency too. These cells pitch off and may establish some where else. Ex. Malignant metastatic cells from Breast cancer tumor pitch off and establishing in bone..

patent US-6288039 cites several enzymes implicated in the metastatic process: metalloproteinases, cysteine proteases and serine proteases of Yagel, S.A. et al., 49 cancer research 3553 (1989) Dicson R.B. 41 Steroid biochem . Molec. Biol 389 (1992) and the patent claims that detecting the amount of phospholipase A2 inhibitor is key to diagnose the prognosis of metastasis.

Nat Med. 2013 Dec 1. doi: 10.1038/nm.3418. [Epub ahead of print]

Self-renewal as a therapeutic target in human colorectal cancer.

Kreso A(1), van Galen P(2), Pedley NM(3), Lima-Fernandes E(4), Frelin C(5), Davis

T(6), Cao L(6), Baiazitov R(6), Du W(6), Sydorenko N(6), Moon YC(6), Gibson L(3),

Wang Y(3), Leung C(3), Iscove NN(7), Arrowsmith CH(8), Szentgyorgyi E(9),

Gallinger S(10), Dick JE(11), O'Brien CA(12).

Author information:

(1)1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario,

Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto,

Ontario, Canada.

(2)Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario,

Canada.

(3)1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario,

Canada. [2] Department of Laboratory Medicine and Pathobiology, University of

Toronto, Toronto, Ontario, Canada.

(4)Structural Genomics Consortium, Toronto, Ontario, Canada.

(5)1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario,

Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto,

Ontario, Canada.

(6)PTC Therapeutics, South Plainfield, New Jersey, USA.

(7)1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario,

Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto,

Ontario, Canada. [3] Department of Immunology, University of Toronto, Toronto,

Ontario, Canada.

(8)1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario,

Canada. [2] Structural Genomics Consortium, Toronto, Ontario, Canada. [3]

Department of Medical Biophysics, University of Toronto, Toronto, Ontario,

Canada.

(9)Department of Pathology, Toronto General Hospital, Toronto, Ontario, Canada.

(10)1] Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada. [2]

Fred Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute,

Mount Sinai Hospital, Toronto, Ontario, Canada.

(11)1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario,

Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto,

Ontario, Canada. [3].

(12)1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario,

Canada. [2] Department of Laboratory Medicine and Pathobiology, University of

Toronto, Toronto, Ontario, Canada. [3] Department of Surgery, Toronto General

Hospital, Toronto, Ontario, Canada. [4].

Tumor recurrence following treatment remains a major clinical challenge. Evidence

from xenograft models and human trials indicates selective enrichment of

cancer-initiating cells (CICs) in tumors that survive therapy. Together with

recent reports showing that CIC gene signatures influence patient survival, these

studies predict that targeting self-renewal, the key 'stemness' property unique

to CICs, may represent a new paradigm in cancer therapy. Here we demonstrate that

tumor formation and, more specifically, human colorectal CIC function are

dependent on the canonical self-renewal regulator BMI-1. Downregulation of BMI-1

inhibits the ability of colorectal CICs to self-renew, resulting in the

abrogation of their tumorigenic potential. Treatment of primary colorectal cancer

xenografts with a small-molecule BMI-1 inhibitor resulted in colorectal CIC loss

with long-term and irreversible impairment of tumor growth. Targeting the

BMI-1-related self-renewal machinery provides the basis for a new therapeutic

approach in the treatment of colorectal cancer.

PMID: 24292392 [PubMed - as supplied by publisher]

Besides the already discussed issue of CUP, Cancer of Unknown Primary, there are many MedLine references with these search words or acronym, Natalie Turner gave a lecture in e-eso, at Sept 5, 2013, about: 'Metabolomics in Cancer. A bench to bedside interaction', Access to e-eso is free, after free registration.

Another e-eso session. 'New paradigms to explain metastasis'; Elizabeth Comem, April 11, 2013.

The question of Josef Kas was: Is there are Markers of Metastatic Cancer Cells?

Since

(i) we observed (published now) some strange phenomenon of protein translocation or mislocalization (for example OCT-3 transporter from cancer cell membrane to nucleus membrane/surface) and

(ii) it seems general phenomenon, because other researchers reported on glial Kir4.1 translocation from membrane to nucleus),

(iii) we visualized that this phenomenon occurs only in cancer cells starting migration from brain tumor (seems metastatic process), but not in the cells inside the tumor!

So, if you/we ask what is a marker for metastasis I suggest to include this translocation phenomenon.

Is it a right way?

@Serguei: Mislocation of proteins is observed almost all the times you do IHC on cancer samples with cytokines accumulating in the nucleus of some but not all cancer samples and other sorts of weired localizations. I'm not aware of systematic studies on this feature of cancers, would be worth investigating

Simple answer: No, to my understanding and until now, there is no single marker, which could identify a metastatic cell. The same seems to be true for stem cells, although thousands of labs appear to use different ways to identify their stem cells, cancer stem cells or metastasis initiating cells. There are so many different cancer types, which might be seen as very different groups (but very different groups may share alsmost identical pathways which should open same treatment for very different subgroups), therefore it is not likely to ever find a specific marker for metastasis. And, at least some cancers may have all the tools to metastasize from the beginning of the cancer, like stem cell can easily migrate to distant sites. I tried to look for mechanisms of metastasis ressembling the physiologic steps involved in leukocyte migration, especially lymphocyte homing: cell adhesion receptors mediate rolling and sticking and chemokines can activate the stronger binding against the blood stream. In fact, I could identify some and confirm other adhesion receptors for such rolling events in cancer cells outside the leukocyte-like cell populations, but found the chemokine activation only on lymphoid tumor cells, i.e. although I had written a research grant in 1999 when I was at STanford university, to check for example breast cancer biopsies for expression of CXCR4 and CCR7, I did not get the grant. Others from the Stanford area published later a Nature paper with my postulates, but the mechanism of action is probably not what I postulated. I later found that even normal tissue of the breast can express CXCR4 and CCR7 receptors, therefore, such markers may not serve as metastasis markers, but could be used for tumor cells to metastasize, if already expressed.

GFP labeled prostate cancer markers: http://www.protean.cz/en/recombinant-proteins/cancer-markers

@Ulrich:  not just a mis-localization of proteins (markers), but particularly OCT and Kir4.1 trans-localization from cell endoplasmic membrane to the nucleus membrane; that  is what I mentioned in metastatic glioblastoma cancer cells. So, I guess this is a kind of self-defence of such cells against chemotherapy because OCT is non-selective transporter that drops into the cells many anti-cancer drugs. Also, Kir4.1 potassium channels are necessary to keep Em potential and thus OCT function. Looks like cancer cells defend themselves against chemotherapy by both ways. That is just my simple hypothesis....

@Serguei: could you elaborate on "metastatic" glioblastoma cancer cells - I thought glioblastomas typically do not metastasize.

@Robert: we observed that after implanting GL261 glioma cells into mouse brain the cells stay together when the tumor growth and tumor mass is increased, but after certain period the glioblastoma cells start (i) invasion in deep brain parenhyma and (ii) these cells translocate organic cation transorter, OCT-3, from plasma membrane to nucleus membrane; (iii) soon after mice die. You can see details of the procedure and results in: Kucheryavykh LY, Rolón-Reyes K, Kucheryavykh YV, Skatchkov S, Eaton MJ, Sanabria P, Wessinger WD, Inyushin M. (2014) Glioblastoma development in mouse brain: general reduction of OCTs and mislocalization of OCT3 transporter and subsequent uptake of ASP+ substrate to the nuclei. J Neurosci Neuroeng; 3(1):3-9.

We do not know the mechanism of OCT-3 translocation. We do not the mechanism of different accumulation of  ASP+ in cytoplasm versus nuclei between core tumor cells and migrating (peripheral) cells.