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edge

Chief of Research
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Reply with quote  #1 

Cancer Stems Cells: The New Front

 

 

Garden of Good and Evil:  Cancer Stem Cells (CSCs)

To understand cancer stem cells (CSCs), - sometimes also called  tumor-initiating cells - it's important to appreciate what a stem cell is.   A  stem cell is a special cell type that, unlike other normal cells, has two critical defining capabilities: (1) self-renewal, which is the ability to reproduce exact copies of itself,  and (2) differentiation, which is the the ability to change  into one of the several different specialized cell types in the body, such as nerve cells, or heart cells, or muscle cells, or immune cells, or digestive tract cells, or blood cells, among numerous others.  Stem cells start out biological blank slates that nonetheless can create a couple of hundred distinct cell types (the special embryonic stem cells being the  stem cells found in the embryo just after conception, disappearing after fulfilling their  function). In contrast with transient embryonic stem cells, adult (normal)  stem cells persist through the human life cycle primarily for the replenishment of specific cell types that are lost or damaged (like the  ever changing cells in the layer  lining the digestive tract). 

 

A Brief Tour of Cancer Stem Cells (CSCs)

Cancer stem cells are considered to arise from normal stem cells, via mutational damage to and/or molecular dysfunction of, normal stem cells. This brings out the fundamental difference between normal stem cells (SCs) and cancer stem cells (CSCs): cancer stem cells exhibit uncontrolled reproduction, and hence may be critical in tumorigenesis, the process of tumor formation, which itself derives from the more primitive process of carcinogenesis, which is the  process by which normal cells are transformed into cancer cells, the accumulation of cancer cells into larger structures called tumors - masses of cancer  cells - being tumorigenesis.  Thus what a cancer  stem cell has over a (normal) stem cell is the additional property of being able to seed or regenerate new tumors.  The Cancer Stem Cell Hypothesis posits that only a small portion of cells are actually capable of becoming cancerous, and this small population of cells in a tumor is responsible for the continuous, uncontrolled growth uniquely seen in cancer. This is in opposition to the traditional view of any cell being able to divide endlessly, and to acquire mutations to support such uncontrolled reproduction.  One authoritative definition therefore of a cancer stem cell comes from the AAACR (American Association of Cancer Research): a cancer stem cell is "a cell within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor".  According to this model, tumors originate from the malignant transformation of an adult stem cell (or offspring/ progenitor) through the dysregulation of an otherwise normally tightly-regulated self-renewal program. 

 

Thus, the small cancer stem cell population of cells within a tumor are essential to tumor growth and survival; the remaining cells within a tumor are considered non-tumorigenic cancer cells.  However here lies a problem.   Cancer stem cells exhibit a relative quiescence (metabolic silence or dormancy) compared to the rapidly proliferating majority of cells in a tumor which have limited ability to proliferate and instead differentiate into cells that form the bulk of the tumor mass.  But this makes cancer stem cells relatively resistant to conventional therapies because these traditional therapies, by definition, target highly proliferating cells, allowing these relatively inactive cancer stem cells to evade the anticancer effects of most oncotherapies.  And given the cancer stem cells' ability  to self-renew and proliferate, they can maintain the tumor even if the other non-cancer stem cells of the tumor are cytoreduced or destroyed.

 


[courtesy Wikimedia Commons]

 

Note that techniques for identifying and isolating cancer stems cells are being refined, with research establishing some cell-surface proteins functioning as biomarkers on cancer Note that cells that exhibit  important stem cell capabilities, these biomarkers being most notably CD44, CD133, and ALDH1, among others.

 

Seed and Soil, and Weeds

Furthermore, even more unfortunately given this, the persistence and long-term survival of treatment-resistant cancer stem cells may account for the recurrence of tumors in patients despite initial improvements.   Finally, cancer stem cells are also efficient repairers of DNA damage and hence in this additional way also evade apoptosis (programmed cell death).  The soil-and-seed (garden) metaphor likens such therapeutic evasion to weeds, where the cancer stem cells are like the hardy roots of the weed, while the majority of the tumor mass is constituted by the leaves and stem of the weed, so that removal of above-soil visible components of the weed only appear to destroy it, but the underground  cancer stem cell roots will inevitably sprout another stem to allow the weed further survival. 

 

Indeed, cancer stem cells are closely tied to drug resistance: they tend to have high levels of certain "cellular pumps" like the multiple drug resistance protein (MDR), these cellular pumps being to push out or eject anticancer drugs from the cells, limiting or nullifying the efficacy of the therapy.  And research suggests that enabling this resistance and evasion of cancer stem cells from cell death (apoptosis) is the exploitation by cancer stem cells of highly primitive underlying pathways (primarily Hedgehog, Wnt ("Wingless"), and Notch, and also to some extent NF-kB and mTOR, among some others). 

 

For example, with these evasion mechanisms, it is strongly suspected, from initial results reported by Duke University  researchers studying glioblastoma (GBM), that some brain tumors may contain small populations of cancer stem cells that may be resistant to radiation therapy; these cancer stem cells, when isolated from brain tumor tissues, can survive radiation therapy despite radiation-induced DNA damage, largely because of the significantly higher efficiency of cancer stem cells, compared to other  cells, for making DNA repairs, against both DNA  damage from chemotherapy as well as radiotherapy, hence enhancing their survival.

 

And even more radically, Ciara O'Brien's Breast Biology Group at the University of Manchester has put forth evidence that breast cancer stem cells may be endocrine resistant because it appears they expresses very little ER-alpha, and hence breast CSCs may be fundamentally causal of resistance to endocrine therapies.  Similarly, the Jules Bordet Institute team of Philippe Bedard, Fatima Cardoso and Martine Piccart-Gebhart have in parallel provided evidence that cancer stem cells may be at the root of resistance of HER-2 targeted therapy, again by  the CSCs use of key stem-cell maintenance pathways, such as Hedgehog, Notch, and Wnt.

 

Where We Stand

Thus, as noted above, recent research into the origins of cancers is converging to suggest that the cancer stem cell is the source of both initial tumor formation and eventual patient relapse/recurrence, and cancer stem cells may be the highly primitive causal agents in tumor initiation, proliferation, progression, metastasis, and relapse, with these cells both initiating and promoting tumorigenesis and seeding the cellular heterogeneity manifest in tumors via unlimited capacity to propagate through self-renewal.  On this view, therefore, there is but one and the same answer to two core questions of oncology:

 

  1. How does cancer develop (carcinogenesis and tumorigenesis)?
  2. Why does cancer recur?

 

and that (Ur-)answer is cancer stem cells (CSCs)

 

Edge-CAM On the Battlefront

Given the above - the critical role of cancer stem cells (CSCs) in carcinogenesis and tumorigenesis, in treatment resistance and patient relapse, the core components of Edge-CAM have been carefully selected over the years in part for their activity against cancer stem cells.  In this connection, the research of Madhuri Kakarala and Max Wicha at  the University Of Michigan Comprehensive Cancer Center suggests that the chemopreventive activity of curcumin (and certain other dietary polyphenols such as EGCG) is in part due to curcumin's regulation and modulation of molecules in the cancer stem cell (CSC) self-renewal pathways, the Hedgehog/Wnt-β catenin and Notch pathways.  More particularly, they examined the activity of Sabinsa-certified curcuminoids + piperine (Bioperine, commercially) on mammosphere formation, ALDH (aldehyde dehydrogenas) expression (which as noted above is a  breast cancer stem cell marker), and Wnt signaling, finding that the curcuminoid + piperine complex inhibits breast stem cell self-renewal, and inhibits Wnt signaling (earlier also demonstrated by Chi Hoon Park and colleagues, and most recently by Chandra Prasad and colleagues in both MCF-7 and MDA-MB-231 (triple negative) cells, among other supporting research), and with negligible or no effect on differentiated cells. 

 

And Yang Liu and colleagues at Peking University demonstrated the activity of another Edge-CAM component, parthenolide, against cancer stem cells (formulated in a special liposomal complex of parthenolide combined with vinorelbine (Navelbine), most likely via epigenetic activities on multiple oncoproteins, along with and p53 activation and HDAC inhibition. And recent research has found that selenium, EGCG, and vitamin D3 are  involved in stem-cell differentiation and may inhibit Wnt signaling, thus suggesting a role as components of a cancer prevention strategy aimed at the stem cell level, while in addition resveratrol appears to affect the CSC-critical Notch pathway at the post-translational level.  Therefore, collectively, curcuminoids/piperine, parthenolide, EGCG, resveratrol, Vitamin D3, and selenium are active against cancer stems cells and hence may be of benefit against


(1) tumor initiation, proliferation, progression, metastasis and patient relapse, as well as against 


(2) drug resistance in a wide variety of tumor types, and also


(3) may block or inhibit the ability of cancer stem cells to evade DNA damage from genotoxic (DNA-damaging) chemotherapies, radiation therapy, and biologicals such as PARP inhibitors.

 

This anti-CSC strategy is in part parallel to, and best understood as, combining traditional chemotherapy with anti-CSC agents:  recent research has shown that low-dose metformin (Glugophage), an anti-diabetes medication, selectively and preferentially targets cancer stem cells, acting with chemotherapy to both block tumor growth and prolong remission and mitigate risk of patient relapse (from Kevin Struhl's seminal findings at  Harvard and Tufts) in four breast cancer cell lines, including hormone/endocrine-positive, HER2-positive, and triple negative breast cancers. The study found that the anthracycline doxorubicin (Adriamycin) was cytotoxic against tumor cells but not against cancer stem cells within the same tumor, these cancer  stem cellls remaining after  doxorubicin treatment, allowing for tumor relapse.  In contrast metformin was highly effective, killing the cancer stem cells, but leaving other non-CSC tumor cells intact, hence also allowing for relapse.  But when metformin was combined with doxorubicin, it eradicated the tumors completely, and prevented recurrence.

 

The Road to the Cure

Thus the cumulative evidence suggests optimal protection from relapse/recurrence via an anti-cancer stem cell (anti-CSC) strategy, especially in conjunction with other anti-cancer therapies, and the anti-CSC activity may come either from traditional agents such as metformin - which operates primarily at the mTOR pathway level - or from anti-CSC natural CAM components, as I motivated above, and may represent a paradigm shift in the treatment with curative intent of both normal tumor, and cancer stem, cells for maximum reduction of relapse risk. 





Constantine Kaniklidis

Breast Cancer Watch

edge@evidencewatch.com

MsBliss

Goddess
Registered:
Posts: 103
Reply with quote  #2 
This analysis needs to be seen by many, many more people.  It is so enlightening and comprehensive.... 

Quote:
Originally Posted by edge

Cancer Stems Cells: The New Front

 

 

Garden of Good and Evil:  Cancer Stem Cells (CSCs)

To understand cancer stem cells (CSCs), - sometimes also called  tumor-initiating cells - it's important to appreciate what a stem cell is.   A  stem cell is a special cell type that, unlike other normal cells, has two critical defining capabilities: (1) self-renewal, which is the ability to reproduce exact copies of itself,  and (2) differentiation, which is the the ability to change  into one of the several different specialized cell types in the body, such as nerve cells, or heart cells, or muscle cells, or immune cells, or digestive tract cells, or blood cells, among numerous others.  Stem cells start out biological blank slates that nonetheless can create a couple of hundred distinct cell types (the special embryonic stem cells being the  stem cells found in the embryo just after conception, disappearing after fulfilling their  function). In contrast with transient embryonic stem cells, adult (normal)  stem cells persist through the human life cycle primarily for the replenishment of specific cell types that are lost or damaged (like the  ever changing cells in the layer  lining the digestive tract). 

 

A Brief Tour of Cancer Stem Cells (CSCs)

Cancer stem cells are considered to arise from normal stem cells, via mutational damage to and/or molecular dysfunction of, normal stem cells. This brings out the fundamental difference between normal stem cells (SCs) and cancer stem cells (CSCs): cancer stem cells exhibit uncontrolled reproduction, and hence may be critical in tumorigenesis, the process of tumor formation, which itself derives from the more primitive process of carcinogenesis, which is the  process by which normal cells are transformed into cancer cells, the accumulation of cancer cells into larger structures called tumors - masses of cancer  cells - being tumorigenesis.  Thus what a cancer  stem cell has over a (normal) stem cell is the additional property of being able to seed or regenerate new tumors.  The Cancer Stem Cell Hypothesis posits that only a small portion of cells are actually capable of becoming cancerous, and this small population of cells in a tumor is responsible for the continuous, uncontrolled growth uniquely seen in cancer. This is in opposition to the traditional view of any cell being able to divide endlessly, and to acquire mutations to support such uncontrolled reproduction.  One authoritative definition therefore of a cancer stem cell comes from the AAACR (American Association of Cancer Research): a cancer stem cell is "a cell within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor".  According to this model, tumors originate from the malignant transformation of an adult stem cell (or offspring/ progenitor) through the dysregulation of an otherwise normally tightly-regulated self-renewal program. 

 

Thus, the small cancer stem cell population of cells within a tumor are essential to tumor growth and survival; the remaining cells within a tumor are considered non-tumorigenic cancer cells.  However here lies a problem.   Cancer stem cells exhibit a relative quiescence (metabolic silence or dormancy) compared to the rapidly proliferating majority of cells in a tumor which have limited ability to proliferate and instead differentiate into cells that form the bulk of the tumor mass.  But this makes cancer stem cells relatively resistant to conventional therapies because these traditional therapies, by definition, target highly proliferating cells, allowing these relatively inactive cancer stem cells to evade the anticancer effects of most oncotherapies.  And given the cancer stem cells' ability  to self-renew and proliferate, they can maintain the tumor even if the other non-cancer stem cells of the tumor are cytoreduced or destroyed.

 


[courtesy Wikimedia Commons]

 

Note that techniques for identifying and isolating cancer stems cells are being refined, with research establishing some cell-surface proteins functioning as biomarkers on cancer Note that cells that exhibit  important stem cell capabilities, these biomarkers being most notably CD44, CD133, and ALDH1, among others.

 

Seed and Soil, and Weeds

Furthermore, even more unfortunately given this, the persistence and long-term survival of treatment-resistant cancer stem cells may account for the recurrence of tumors in patients despite initial improvements.   Finally, cancer stem cells are also efficient repairers of DNA damage and hence in this additional way also evade apoptosis (programmed cell death).  The soil-and-seed (garden) metaphor likens such therapeutic evasion to weeds, where the cancer stem cells are like the hardy roots of the weed, while the majority of the tumor mass is constituted by the leaves and stem of the weed, so that removal of above-soil visible components of the weed only appear to destroy it, but the underground  cancer stem cell roots will inevitably sprout another stem to allow the weed further survival. 

 

Indeed, cancer stem cells are closely tied to drug resistance: they tend to have high levels of certain "cellular pumps" like the multiple drug resistance protein (MDR), these cellular pumps being to push out or eject anticancer drugs from the cells, limiting or nullifying the efficacy of the therapy.  And research suggests that enabling this resistance and evasion of cancer stem cells from cell death (apoptosis) is the exploitation by cancer stem cells of highly primitive underlying pathways (primarily Hedgehog, Wnt ("Wingless"), and Notch, and also to some extent NF-kB and mTOR, among some others). 

 

For example, with these evasion mechanisms, it is strongly suspected, from initial results reported by Duke University  researchers studying glioblastoma (GBM), that some brain tumors may contain small populations of cancer stem cells that may be resistant to radiation therapy; these cancer stem cells, when isolated from brain tumor tissues, can survive radiation therapy despite radiation-induced DNA damage, largely because of the significantly higher efficiency of cancer stem cells, compared to other  cells, for making DNA repairs, against both DNA  damage from chemotherapy as well as radiotherapy, hence enhancing their survival.

 

And even more radically, Ciara O'Brien's Breast Biology Group at the University of Manchester has put forth evidence that breast cancer stem cells may be endocrine resistant because it appears they expresses very little ER-alpha, and hence breast CSCs may be fundamentally causal of resistance to endocrine therapies.  Similarly, the Jules Bordet Institute team of Philippe Bedard, Fatima Cardoso and Martine Piccart-Gebhart have in parallel provided evidence that cancer stem cells may be at the root of resistance of HER-2 targeted therapy, again by  the CSCs use of key stem-cell maintenance pathways, such as Hedgehog, Notch, and Wnt.

 

Where We Stand

Thus, as noted above, recent research into the origins of cancers is converging to suggest that the cancer stem cell is the source of both initial tumor formation and eventual patient relapse/recurrence, and cancer stem cells may be the highly primitive causal agents in tumor initiation, proliferation, progression, metastasis, and relapse, with these cells both initiating and promoting tumorigenesis and seeding the cellular heterogeneity manifest in tumors via unlimited capacity to propagate through self-renewal.  On this view, therefore, there is but one and the same answer to two core questions of oncology:

 

  1. How does cancer develop (carcinogenesis and tumorigenesis)?
  2. Why does cancer recur?

 

and that (Ur-)answer is cancer stem cells (CSCs)

 

Edge-CAM On the Battlefront

Given the above - the critical role of cancer stem cells (CSCs) in carcinogenesis and tumorigenesis, in treatment resistance and patient relapse, the core components of Edge-CAM have been carefully selected over the years in part for their activity against cancer stem cells.  In this connection, the research of Madhuri Kakarala and Max Wicha at  the University Of Michigan Comprehensive Cancer Center suggests that the chemopreventive activity of curcumin (and certain other dietary polyphenols such as EGCG) is in part due to curcumin's regulation and modulation of molecules in the cancer stem cell (CSC) self-renewal pathways, the Hedgehog/Wnt-β catenin and Notch pathways.  More particularly, they examined the activity of Sabinsa-certified curcuminoids + piperine (Bioperine, commercially) on mammosphere formation, ALDH (aldehyde dehydrogenas) expression (which as noted above is a  breast cancer stem cell marker), and Wnt signaling, finding that the curcuminoid + piperine complex inhibits breast stem cell self-renewal, and inhibits Wnt signaling (earlier also demonstrated by Chi Hoon Park and colleagues, and most recently by Chandra Prasad and colleagues in both MCF-7 and MDA-MB-231 (triple negative) cells, among other supporting research), and with negligible or no effect on differentiated cells. 

 

And Yang Liu and colleagues at Peking University demonstrated the activity of another Edge-CAM component, parthenolide, against cancer stem cells (formulated in a special liposomal complex of parthenolide combined with vinorelbine (Navelbine), most likely via epigenetic activities on multiple oncoproteins, along with and p53 activation and HDAC inhibition. And recent research has found that selenium, EGCG, and vitamin D3 are  involved in stem-cell differentiation and may inhibit Wnt signaling, thus suggesting a role as components of a cancer prevention strategy aimed at the stem cell level, while in addition resveratrol appears to affect the CSC-critical Notch pathway at the post-translational level.  Therefore, collectively, curcuminoids/piperine, parthenolide, EGCG, resveratrol, Vitamin D3, and selenium are active against cancer stems cells and hence may be of benefit against


(1) tumor initiation, proliferation, progression, metastasis and patient relapse, as well as against 


(2) drug resistance in a wide variety of tumor types, and also


(3) may block or inhibit the ability of cancer stem cells to evade DNA damage from genotoxic (DNA-damaging) chemotherapies, radiation therapy, and biologicals such as PARP inhibitors.

 

This anti-CSC strategy is in part parallel to, and best understood as, combining traditional chemotherapy with anti-CSC agents:  recent research has shown that low-dose metformin (Glugophage), an anti-diabetes medication, selectively and preferentially targets cancer stem cells, acting with chemotherapy to both block tumor growth and prolong remission and mitigate risk of patient relapse (from Kevin Struhl's seminal findings at  Harvard and Tufts) in four breast cancer cell lines, including hormone/endocrine-positive, HER2-positive, and triple negative breast cancers. The study found that the anthracycline doxorubicin (Adriamycin) was cytotoxic against tumor cells but not against cancer stem cells within the same tumor, these cancer  stem cellls remaining after  doxorubicin treatment, allowing for tumor relapse.  In contrast metformin was highly effective, killing the cancer stem cells, but leaving other non-CSC tumor cells intact, hence also allowing for relapse.  But when metformin was combined with doxorubicin, it eradicated the tumors completely, and prevented recurrence.

 

The Road to the Cure

Thus the cumulative evidence suggests optimal protection from relapse/recurrence via an anti-cancer stem cell (anti-CSC) strategy, especially in conjunction with other anti-cancer therapies, and the anti-CSC activity may come either from traditional agents such as metformin - which operates primarily at the mTOR pathway level - or from anti-CSC natural CAM components, as I motivated above, and may represent a paradigm shift in the treatment with curative intent of both normal tumor, and cancer stem, cells for maximum reduction of relapse risk. 





Constantine Kaniklidis

Breast Cancer Watch

edge@evidencewatch.com

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