April 30, 2013 by

The dual effect of MSCs on tumour growth and tumour angiogenesis

Michelle Kéramidas, Florence de Fraipont, Anastassia Karageorgis, Anaïck Moisan, Virginie Persoons, Marie-Jeanne Richard, Jean-Luc Coll and Claire Rome

Abstract (provisional)
Introduction

Understanding the multiple biological functions played by human mesenchymal stem cells (hMSCs) as well as their development as therapeutics in regenerative medicine or in cancer treatment are major fields of research. Indeed, it has been established that hMSCs play a central role in the pathogenesis and progression of tumours, but their impact on tumour growth remains controversial.

Our results suggest that hMSCs injection decreased solid tumour growth in mice and modified tumour vasculature, which confirms hMSCs could be interesting to use for the treatment of pre-established tumours.

Methods

In this study, we investigated the influence of hMSCs on the growth of pre-established tumours. We engrafted nude mice with luciferase-positive mouse adenocarcinoma cells (TSA-Luc+) to obtain subcutaneous or lung tumours. When tumour presence was confirmed by non-invasive bioluminescence imaging, hMSCs were injected into the periphery of the SC tumours or delivered by systemic intravenous injection in mice bearing either SC tumours or lung metastasis.

Results

Regardless of the tumour model and mode of hMSC injection, hMSC administration was always associated with decreased tumour growth due to an inhibition of tumour cell proliferation, likely resulting from deep modifications of the tumour angiogenesis. Indeed, we established that although hMSCs can induce the formation of new blood vessels in a non-tumoural cellulose sponge model in mice, they do not modify the overall amount of haemoglobin delivered into the SC tumours or lung metastasis. We observed that these tumour vessels were reduced in number but were longer.

Conclusions

Our results suggest that hMSCs injection decreased solid tumour growth in mice and modified tumour vasculature, which confirms hMSCs could be interesting to use for the treatment of pre-established tumours.

Original Link: http://stemcellres.com/content/4/2/41/abstract

Filed Under: Cancer, Mesenchymal Stem Cells, News, Stem Cell Research Tagged With: , , , , , ,
December 29, 2010 by

Resveratrol Suppresses Cancer Stem Cells

Pandey et al. Breast Cancer Res Treat.

Resveratrol is a compound found in grapes, red wine, purple grape juice, peanuts, and berries that has been associated with many health benefits, particularly reduction in heart disease. Some studies have demonstrated that resveratrol increases life span when administered at high concentrations. One area of controversy has been the potential of resveratrol in the treatment of cancer.

One way of testing the anti-cancer efficacy of compounds is to administer the compound of interest to cancer cells that are growing “in a test tube”, or “in vitro.” Recently it was shown that cancer cells taken from a patient and propagated in vitro are usually not representative of the original tumor from which the cancer cells were excised. Specifically, it has been shown that in patients, cancer cells can broadly be classified into the rapidly multiplying cells, and the “sleeping cells” otherwise known as tumor stem cells. It appears that in vitro the rapidly multiplying cells continue multiplying, but the cancer stem cells do not multiply. This is important because the cancer stem cells seem to be the cells responsible for causing the tumor to spread, whereas in the rapidly multiplying cells actually seem to be weaker and more sensitive to chemotherapy.

To date the majority of studies investigating effects of resveratrol on cancer have focused on testing with the rapidly multiplying cells. The paper published today investigated the effects of resveratrol on tumor stem cells. Breast cancer tumor stem cells where isolated based on expression of the proteins CD44 and ESA, and lacking CD24. Tumor stem cells were harvested from patients that were both estrogen receptor positive and negative. It was found that addition of resveratrol caused death of the tumor stem cells, as well as blocked their ability to form three dimensional tumors in tissue culture called “mammospheres.”

Interestingly it seemed like the effects of the resveratrol were mediated by manipulating the way in which the cancer stem cells make fat. Specifically, resveratrol caused a significant reduction in fat synthesis which is associated with down-regulation of the enzyme fatty acid synthase (FAS). The suppression of the enzyme FAS was correlated with upregulation of the genes DAPK2 and BNIP3, which are known to stimulate a process called “apoptosis”, or cellular suicide.

This recent paper belongs to a growing example of scientific reports in which various “treatments” advocated by naturopathic doctors seem to have effects on cancer stem cells. For example, a previous publication (Kakarala et al. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat. 2010 Aug;122(3):777-85.) reported that the chemical curcumin, which is a component of the Indian spice turmeric, selectively inhibits cancer stem cells.

It appears that many of the chemotherapeutic drugs that are conventionally used in the treatment of cancer do not affect the cancer stem cell because chemotherapy requires tumor cells to be actively proliferating. In contrast, many of the “natural remedies” seem to suppress cancer stem cells because their activities seem to be mediated by other means than the ones in which chemotherapy works. It will be interesting to see if more papers such as the present one appear, which seem to provide scientific rationale for a more “compassionate approach” to cancer therapy

Filed Under: Cancer, News, Stem Cell Research Tagged With: , , , , ,
August 1, 2010 by

Pluripotent stem cell-derived natural killer cells for cancer therapy.

Knorr et al. Transl Res. 2010 Sep;156(3):147-154. Epub

Immune therapy of cancer is an exciting prospect given the possibility of treating cancer without the side effects associated with conventional treatments such as chemotherapy or radiotherapy. Additionally, the use of the immune system to target tumors offers the possibility of eradicating micrometastasis, which often cannot be treated by conventional means.

Early work in the immunotherapy of cancer involved taking out patient lymphocytes that were infiltrating the tumor, expanding them outside of the body, and subsequently re-injecting them with the hope that expanded numbers of tumor-specific killer cells would destroy the tumor. Unfortunately this approach was very expensive and did not yield positive results to justify the complexity and expense of the procedure. One possible reason for the failure of this approach is that the cells used where already “old” and “exhausted”. In other words, previous encounters of the T cells with cancer antigens seems to have programmed them so as to inhibit ability to mount a proper immune response.

The use of natural killer cells as an alternative to T cells was considered. These cells, called lymphokine activated killers (LAK) displayed specific ability to kill tumors and were more effective than T cells alone. Unfortunately this approach too also required substantial manipulation of the cells outside of the body and was not practical.

In a recent paper, the group of Knorr et al discussed how to use stem cells to solve the problem of generating anti-cancer immune cells out of the body. They discuss how they have successfully used embryonic stem cells to generate “universal donor” natural killer cells. This approach is highly promising since NK cells do not need to be matched with the recipient in order to mediate anti-cancer activity. Additionally, since the cells are generated “brand new” in the laboratory, the problem of “exhaustion” is no longer relevant. Unfortunately there are still several obstacles to overcome such as the potential of embryonic stem cells forming leukemias/tumors, and the possibility of host anti-graft responses.

The paper also describes the future possibility of using inducible pluripotent stem (iPS) cells as a method of generating autologous T cells with any given TCR specificity.

Filed Under: Cancer, News, Stem Cell Research Tagged With: , , ,
May 11, 2010 by

Natural Compound in Broccoli Slows Breast Cancer Stem Cells

The area of cancer stem cells is very hot. To give an
example, the pharmaceutical company GSK recently purchased the cancer stem cell
company Oncomed for more than a billion dollars, at a time when Oncomed’s cancer
stem cell-targeting drugs were not even tested in humans. This area is of great
interest because it suggests that the way to kill cancer is not to block the
fast multiplying cells, but that the cancer has a "root cause" that scientists
for decades have been ignoring.

Cancer stem cells are usually not destroyed by chemotherapy
or radiation therapy because they are slow dividing cells that possess numerous
proteins to protect themselves from toxicity such as multiple drug resistance
proteins. These proteins have the function of identifying chemotherapy inside
of the cancer cell and actively pumping it out. It is believed that the reason
why these proteins exist is to protect cells from damage to DNA. In cancer stem
cells these proteins appear to play a role in causing relapse after
chemotherapy.

Previously it was reported that the chicken feed antibiotic
salinomycin has the ability to selectively kill cancer stem cells (Gupta PB.
Identification of selective inhibitors of cancer stem cells by high-throughput
screening. Cell. 2009 Aug 21;138(4):645-59. Epub 2009 Aug 13), additionally,
using similar testing scenarios researchers found the anti-diabetic drug
metfomin inhibits breast cancer stem cells (Vazquez-Martin et al. The
anti-diabetic drug metformin suppresses self-renewal and proliferation of
trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer
Res Treat. 2010 May 11). Given the recent nature of these findings, their
use in humans has not yet been reported in the scientific literature. In the
current study which will be discussed, another compound with similar anti-breast
cancer stem cell activity was identified.

A recent study (Li et al. Sulforaphane, a dietary
component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin
Cancer Res. 2010 May 1;16(9):2580-90) demonstrated that a natural chemical
compound found in broccoli and other cruciferous vegetables called sulforaphane
has the ability to slow down multiplication of breast cancer stem cells.
Essentially this means that sulforaphane can block the cells that cause cancer
from being activated and thus could be an effective cancer therapy if high
enough doses can be safely administered.

The scientists purified human breast cancer stem cells
using the Aldefluor assay made by the company Aldagen, which selects for cells
expressing the enzyme aldehyde dehydrogenase, an enzyme found in normal and
cancer stem cells. The stem cells were tested to see if they would form tumors
in mice lacking an immune system called nonobese diabetic/severe combined
immunodeficient mice.

It was found that sulforaphane administered at a
concentration of 1-5 micromol/L was sufficient to suppress multiplication of the
aldehyde dehydrogenase-positive stem cell population by 65% to 80% and reduce
the size and number of primary mammospheres by 8- to 125-fold and 45% to 75%,
respectively. Mammospheres are round tumor-like structures that grow in tissue
culture plates that represent a three-dimensional cancer.

Daily injection with 50 mg/kg sulforaphane for 2 weeks
reduced aldehyde dehydrogenase-positive cells by >50% in nonobese
diabetic/severe combined immunodeficient xenograft tumors. Since it appeared
that the administration of sulforaphane eliminated breast cancer stem cells in
the animal, the next step was to assess the ability of the growing tumors to
cause secondary tumors when transplanted into other animals. This indeed was
demonstrated to be the case. Ability to block transfer of tumors to secondary
recipients is associated with possibility of cure since it represents targeting
of the functional tumor stem cell compartment.

Mechanistically it appears that sulforaphane works on the
cancer stem cells through suppression of the Wnt/beta-catenin self-renewal
pathway, which is found in numerous tumor and non-malignant stem cells. This of
course poses the question of whether the high doses of sulforaphane that were
used in the study would have unwanted effects on healthy stem cells in the
body. The most relevant side effect of chemotherapeutic drugs is suppression of
blood cell production from the bone marrow stem cell. Indeed the scientists
found that there was no alteration of blood cell parameters in treated animals,
suggesting at least a partial degree of selectivity.

Sulforaphane is believed to exert at least some of its
anticancer biological effects through its ability to suppress histone
deacetylase (HDAC) activity. HDAC are proteins that are involved in "bundling"
of the DNA. If DNA from one cell was stretched out, it would be 7 meters from
end-to-end. The histone that are acetylated bind DNA in a loose manner and
allow for new genes from the DNA to be expressed that normally would not be
expressed. In the area of cancer, the treatment with HDAC inhibitors is
believed to cause brand new expression of tumor suppressor genes. These genes,
such as p53, instruct the tumor cell to undergo cellular suicide, called
apoptosis.

The controversial "Burzynski Therapy" involving
antineoplastons, which are naturally occurring compounds is believed to function
through induction of histone acetylation and induction of tumor suppressor genes
(Burzynski, The present state of antineoplaston research, Integr Cancer Ther.
2004 Mar;3(1):47-58). It would be interesting to examine whether some of the
reported positive effects of this non-toxic cancer therapy is mediated by
suppression of tumor stem cell activity.

A recent paper (Ho et al. Dietary sulforaphane, a
histone deacetylase inhibitor for cancer prevention. J Nutr. 2009
Dec;139(12):2393-6. Epub 2009 Oct 7) demonstrated that sulforaphane inhibits
HDAC activity in human colorectal and prostate cancer cells. Based on the
similarity of sulforaphane metabolites and other phytochemicals to known HDAC
inhibitors, it was previously demonstrated that sulforaphane acted as an HDAC
inhibitor in the prostate, causing enhanced histone acetylation, derepression of
P21 and Bax, and induction of cell cycle arrest/apoptosis, leading to cancer
prevention. The possible ability of sulforaphane to target aberrant acetylation
patterns, in addition to effects on phase 2 enzymes, may make it an effective
agent in suppressing cancer cells in a non-toxic manner.

This study also poses the question if HDAC inhibitors in
general can alter tumor stem cell ability. It is known that valproic acid, the
HDAC inhibitor actually increases ability of stem cells to self renew while
being selectively toxic to leukemic cells

http://www.youtube.com/watch?v=3Hc4LCUOSiA.

An interesting note regarding cancer stem cells is that many approaches
traditionally supported by practitioners of alternative medicine may actually be
targeting these cells. In alternative medicine the main theme is providing the
body with nutrients to "heal itself". Practitioners of alternative medicine
have had some degree of success treating cancer in a "nontoxic" manner using
dramatic dietary modifications, nutrient therapy, and administration of agents
that induce differentiation. It may be possible that these interventions act to
reduce the localized inflammation in the tumor mass. This inflammation is
believed by some to be what stimulates the cancer stem cell to enter cell
cycle. Accordingly, it is interesting to see that components of broccoli
inhibit cancer stem cells. It will be interesting to examine other nutrients
for ability to target cancer stem cells.

Filed Under: Cancer, News, Stem Cell Research Tagged With: , , , ,