I've been reading profusely since diagnosed with MGUS 3 months ago. This weekend I came across an article of great concern to me as it states that thyroid hormones, particularly T4, induce cultured myeloma cell proliferation (via MAPK activation). I have Hashimoto's disease and have been on thyroid medication for at least 5 years. Could this be what triggered my MGUS?
Here's the reference.
[1] K Cohen et al, "Thyroid hormone is a MAPK-dependent growth factor for human myeloma cells acting via αvβ3 integrin," Molecular Cancer Research, October 2011, 9(10):1385-94 (full text pdf).
Abstract:
Experimental and clinical observations suggest that thyroid hormone [l-thyroxine (T(4)) and 3,5,3'-triiodo-l-thyronine (T(3))] can support cancer cell proliferation. T(3) and T(4) promote both tumor cell division and angiogenesis by activating mitogen-activated protein kinase (MAPK) via binding to a hormone receptor on the αvβ3 integrin, overexpressed on many cancer cells. We have studied the responsiveness of several multiple myeloma cell lines to T(3) and T(4) and characterized hormonal effects on cell survival, proliferation, and MAPK activation. Overnight T(3) (1-100 nmol/L) and T(4) (100 nmol/L) incubation enhanced, up to 50% (P < 0.002), multiple myeloma cell viability (WST-1 assay) and increased cell proliferation by 30% to 60% (P < 0.01). Short exposure (10 minutes) to T(3) and T(4) increased MAPK activity by 2.5- to 3.5-fold (P < 0.03). Pharmacologic MAPK inhibition blocked the proliferative action of T(3) and T(4). Antibodies to the integrin αvβ3 dimer and αv and β3 monomers (but not β1) inhibited MAPK activation and subsequent cell proliferation in response to thyroid hormone, indicating dependence upon this integrin. Moreover, tetraiodothyroacetic acid (tetrac), a non-agonist T(4) analogue previously shown to selectively block T(3)/T(4) binding to αvβ3 receptor site, blocked induction of MAPK by the hormones in a dose-dependent manner. This demonstration of the role of thyroid hormones as growth factors for multiple myeloma cells may offer novel therapeutic approaches.
Forums
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Spanish Mary - Name: Spanish Mary
- Who do you know with myeloma?: Self, MGUS
- When were you/they diagnosed?: May 2014
- Age at diagnosis: 59
Re: Thyroid hormones and multiple myeloma
I would be very interested to hear what the consensus is on this. I have been treated for over 20 years with Synthroid (levothyroxine) to manage hypothyroidism.
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Toni - Name: Toni
- Who do you know with myeloma?: self - MGUS
- When were you/they diagnosed?: April 2014
- Age at diagnosis: 51
Re: Thyroid hormones and multiple myeloma
Hi Toni,
I am so concerned that I've decided to go off my Diotroxin (thyroxine and liothyronine) for 5 weeks, until my next blood tests, to see if it has any effect on my markers. I shall report back!
I am so concerned that I've decided to go off my Diotroxin (thyroxine and liothyronine) for 5 weeks, until my next blood tests, to see if it has any effect on my markers. I shall report back!
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Spanish Mary - Name: Spanish Mary
- Who do you know with myeloma?: Self, MGUS
- When were you/they diagnosed?: May 2014
- Age at diagnosis: 59
Re: Thyroid hormones and multiple myeloma
How do you feel going off of it?
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Toni - Name: Toni
- Who do you know with myeloma?: self - MGUS
- When were you/they diagnosed?: April 2014
- Age at diagnosis: 51
Re: Thyroid hormones and multiple myeloma
It has only been 24 hours and already I am feeling the cold (my husband is in shorts and a T-shirt and I'm wearing jeans and a jersey). I am generally very healthy, never get a cold or flu, so hopefully my 5 weeks will proceed without incident. I have decided to start walking to compensate for the slowdown in metabolism, so hope not to gain weight either.
Emotionally, I feel that I have taken charge of something in this confounding condition where we seem to be in charge of nothing. My doctor will probably not be too pleased with me, but it is just something I have to do.
Emotionally, I feel that I have taken charge of something in this confounding condition where we seem to be in charge of nothing. My doctor will probably not be too pleased with me, but it is just something I have to do.
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Spanish Mary - Name: Spanish Mary
- Who do you know with myeloma?: Self, MGUS
- When were you/they diagnosed?: May 2014
- Age at diagnosis: 59
Re: Thyroid hormones and multiple myeloma
I understand where you are coming from. However, I would probably agree with your doctor. The thyroid is a rather tricky gland to fiddle with 
I am on Synthroid and one time they switched me to a generic. Within a matter of only a day or two, I began feeling cold, overwhelming fatigue, somnolence, etc. I made sure they never switched my Synthroid again. This is one of those cases where generic is not the same. (I think that is true for some heart, epilepsy, and a few other classes of medications?).
Just be cautious. You don't want to encounter any untoward events while ill anyway. I have not read any of the studies re: thyroid and multiple myeloma and to my understanding, this is not a large area of study, at least not yet.
All the best!
I am on Synthroid and one time they switched me to a generic. Within a matter of only a day or two, I began feeling cold, overwhelming fatigue, somnolence, etc. I made sure they never switched my Synthroid again. This is one of those cases where generic is not the same. (I think that is true for some heart, epilepsy, and a few other classes of medications?).Just be cautious. You don't want to encounter any untoward events while ill anyway. I have not read any of the studies re: thyroid and multiple myeloma and to my understanding, this is not a large area of study, at least not yet.
All the best!
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Toni - Name: Toni
- Who do you know with myeloma?: self - MGUS
- When were you/they diagnosed?: April 2014
- Age at diagnosis: 51
Re: Thyroid hormones and multiple myeloma
The authors of the study mentioned by Spanish Mary have also written subsequent papers about the potential impact of thyroid hormones on myeloma cells. We include references to the studies below.
Some of the authors of these papers, by the way, have done similar research in regard to thyroid hormones and their potential to promote the growth of other types of cancer cells, not just myeloma cells.
Also, please note that all of these studies are pre-clinical studies. They look at the impact of thyroid hormones on the growth of myeloma cell lines in a laboratory setting. None of the findings are based on tests administered to patients who have either MGUS, smoldering myeloma, or MGUS and are taking thyroid hormones. Nor have any of the studies investigated the impact of thyroid hormones on myeloma cells in laboratory animals, such as mice or rats.
Some of these studies, by the way, were previously discussed (briefly) in this Beacon forum thread.
We have asked a couple of the Beacon's Medical Advisors for their thoughts on these studies. We expect that one or more of them will share their perspectives in the coming days.
Here are the references to the two additional studies:
[2] K Cohen et al., "Relevance of the thyroid hormones–αvβ3 pathway in primary myeloma bone marrow cells and to bortezomib action," Leukemia & Lymphoma, 2014.
Abstract:
Thyroid hormones (T3 and T4) induce proliferation in multiple myeloma (multiple myeloma) cell lines via the αvβ3 integrin–mitogen-activated protein kinase (MAPK) pathway. We further show in primary multiple myeloma bone marrow (BM) samples (n = 9) induction of cell viability by 1 nM T3 (13%, p < 0.002) and more potently by 100 nM T4 (21–45%, p < 0.0002) and a quick (1 h) and long-lasting (24 h) pERK activation, which was inhibited in the presence of β3 but not β1 blocking antibodies. Involvement of the integrin was further shown by two disintegrins, Arg-Gly-Asp (RGD) and echistatin peptides, which occluded the effects of T3/T4 on viability, proliferating cell nuclear antigen (PCNA) (proliferation marker) and apoptotic gene expression. Lastly, T3/T4 significantly opposed bortezomib (25 nM) cytotoxicy, as confirmed by several methods. In summary, our results imply that endogenous thyroid hormones in myeloma are factors that may support cell growth, with relevance to bortezomib action.
[3] K Cohen et al, "Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via αvβ3 integrin in myeloma cells," Oncotarget, Aug 30, 2014; 5(15):6312-22 (full text online; full text pdf also available)
Abstract:
Thyroid hormone (3,5,3’-triiodothyronine, T3; L-thyroxine, T4) enhances cancer cell proliferation, invasion and angiogenesis via a discrete receptor located near the RGD recognition site on αvβ3 integrin. Tetraiodothyroacetic acid (tetrac) and its nanoparticulate formulation interfere with binding of T3/T4 to the integrin. This integrin is overexpressed in multiple myeloma (multiple myeloma) and other cancers. multiple myeloma cells interact with αvβ3 integrin to support growth and invasion. Matrix metalloproteinases (MMPs) are a family of enzymes active in tissue remodeling and cancer. The association between integrins and MMPs secretion and action is well established. In the current study, we examined the effects of thyroid hormone on myeloma cell adhesion, migration and MMP activity.
We show that T3 and T4 increased myeloma adhesion to fibronectin and induced αvβ3 clustering. In addition, the hormones induced MMP-9 expression and activation via αvβ3 and MAPK induction. Bortezomib, a standard myeloma treatment, caused a decrease in activity/quantity of MMPs and thyroid hormone opposed this effect. RGD peptide and tetrac impaired the production of MMP-9 in cell lines and in primary BM cells from myeloma patients.
In conclusion, thyroid hormone-dependent regulation via αvβ3 of myeloma cell adhesion and MMP-9 production may play a role in myeloma migration and progression.
Some of the authors of these papers, by the way, have done similar research in regard to thyroid hormones and their potential to promote the growth of other types of cancer cells, not just myeloma cells.
Also, please note that all of these studies are pre-clinical studies. They look at the impact of thyroid hormones on the growth of myeloma cell lines in a laboratory setting. None of the findings are based on tests administered to patients who have either MGUS, smoldering myeloma, or MGUS and are taking thyroid hormones. Nor have any of the studies investigated the impact of thyroid hormones on myeloma cells in laboratory animals, such as mice or rats.
Some of these studies, by the way, were previously discussed (briefly) in this Beacon forum thread.
We have asked a couple of the Beacon's Medical Advisors for their thoughts on these studies. We expect that one or more of them will share their perspectives in the coming days.
Here are the references to the two additional studies:
[2] K Cohen et al., "Relevance of the thyroid hormones–αvβ3 pathway in primary myeloma bone marrow cells and to bortezomib action," Leukemia & Lymphoma, 2014.
Abstract:
Thyroid hormones (T3 and T4) induce proliferation in multiple myeloma (multiple myeloma) cell lines via the αvβ3 integrin–mitogen-activated protein kinase (MAPK) pathway. We further show in primary multiple myeloma bone marrow (BM) samples (n = 9) induction of cell viability by 1 nM T3 (13%, p < 0.002) and more potently by 100 nM T4 (21–45%, p < 0.0002) and a quick (1 h) and long-lasting (24 h) pERK activation, which was inhibited in the presence of β3 but not β1 blocking antibodies. Involvement of the integrin was further shown by two disintegrins, Arg-Gly-Asp (RGD) and echistatin peptides, which occluded the effects of T3/T4 on viability, proliferating cell nuclear antigen (PCNA) (proliferation marker) and apoptotic gene expression. Lastly, T3/T4 significantly opposed bortezomib (25 nM) cytotoxicy, as confirmed by several methods. In summary, our results imply that endogenous thyroid hormones in myeloma are factors that may support cell growth, with relevance to bortezomib action.
[3] K Cohen et al, "Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via αvβ3 integrin in myeloma cells," Oncotarget, Aug 30, 2014; 5(15):6312-22 (full text online; full text pdf also available)
Abstract:
Thyroid hormone (3,5,3’-triiodothyronine, T3; L-thyroxine, T4) enhances cancer cell proliferation, invasion and angiogenesis via a discrete receptor located near the RGD recognition site on αvβ3 integrin. Tetraiodothyroacetic acid (tetrac) and its nanoparticulate formulation interfere with binding of T3/T4 to the integrin. This integrin is overexpressed in multiple myeloma (multiple myeloma) and other cancers. multiple myeloma cells interact with αvβ3 integrin to support growth and invasion. Matrix metalloproteinases (MMPs) are a family of enzymes active in tissue remodeling and cancer. The association between integrins and MMPs secretion and action is well established. In the current study, we examined the effects of thyroid hormone on myeloma cell adhesion, migration and MMP activity.
We show that T3 and T4 increased myeloma adhesion to fibronectin and induced αvβ3 clustering. In addition, the hormones induced MMP-9 expression and activation via αvβ3 and MAPK induction. Bortezomib, a standard myeloma treatment, caused a decrease in activity/quantity of MMPs and thyroid hormone opposed this effect. RGD peptide and tetrac impaired the production of MMP-9 in cell lines and in primary BM cells from myeloma patients.
In conclusion, thyroid hormone-dependent regulation via αvβ3 of myeloma cell adhesion and MMP-9 production may play a role in myeloma migration and progression.
Re: Thyroid hormones and multiple myeloma
Thank you so much, Myeloma Beacon, for your thorough and informative response. I will be sure to spend some time reading these studies and taking them under consideration. I had not realized there was a thyroid / cancer correlation, so I look forward to becoming far more informed.
Kind regards,
Toni
Kind regards,
Toni
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Toni - Name: Toni
- Who do you know with myeloma?: self - MGUS
- When were you/they diagnosed?: April 2014
- Age at diagnosis: 51
Re: Thyroid hormones and multiple myeloma
Glad to be of help Toni.
Regarding our statement earlier that
We did not mean for that statement to imply that there is, as you wrote, a "thyroid / cancer correlation." We simply wanted to make clear that the myeloma-related research the authors have done is part of a broader set of research they've been doing looking at the potential impact of thyroid hormones on cancer cells.
Almost all of those studies, as best we can tell, involve pre-clinical research, as is the case with the myeloma-related research the authors have done.
So we don't think it's really correct to suggest that these studies, together, suggest a "thyroid / cancer correlation." Indeed, we have the impression that some researchers might feel that finding similar pre-clinical outcomes in a wide range of cancers may actually lessen the likelihood of there being a clinically meaningful effect of thyroid hormones in any specific cancer – such as myeloma.
That may seem counter-intuitive. But it's the sense we've gotten from some preliminary discussions we have had about these results.
Regarding our statement earlier that
Some of the authors of these papers, by the way, have done similar research in regard to thyroid hormones and their potential to promote the growth of other types of cancer cells, not just myeloma cells.
We did not mean for that statement to imply that there is, as you wrote, a "thyroid / cancer correlation." We simply wanted to make clear that the myeloma-related research the authors have done is part of a broader set of research they've been doing looking at the potential impact of thyroid hormones on cancer cells.
Almost all of those studies, as best we can tell, involve pre-clinical research, as is the case with the myeloma-related research the authors have done.
So we don't think it's really correct to suggest that these studies, together, suggest a "thyroid / cancer correlation." Indeed, we have the impression that some researchers might feel that finding similar pre-clinical outcomes in a wide range of cancers may actually lessen the likelihood of there being a clinically meaningful effect of thyroid hormones in any specific cancer – such as myeloma.
That may seem counter-intuitive. But it's the sense we've gotten from some preliminary discussions we have had about these results.
Re: Thyroid hormones and multiple myeloma
You can't get rid of T3 and T4. Every cell in the human body relies on thyroid hormones for survival, including healthy ones.
I have heard that being hypothyroid increases one's risk for cancer (slow metabolism increases oxidative stress, et al, which relates to DNA damage), and as a matter of fact my primary physician told me that he believes part of the reason I developed multiple myeloma was because my body isn't absorbing what it needs. Hence, I'm on a high dose of desiccated thyroid.
(I was on synthetic thyroid for 15 years before multiple myeloma diagnosis and then switched to desiccated. I actually finally found a doctor who would prescribe desiccated, but my appointment had to be postponed because, unbeknownst to me at the time, the problems I had would lead to a multiple myeloma diagnosis.)
I just keep trying to get down to the basic, basic level of what is going on -- as well as a layman can. I see a lot coming out on oxidative stress and MTHFR, hoping there will be more coming out on these in regards to multiple myeloma, remission, etc.
I have heard that being hypothyroid increases one's risk for cancer (slow metabolism increases oxidative stress, et al, which relates to DNA damage), and as a matter of fact my primary physician told me that he believes part of the reason I developed multiple myeloma was because my body isn't absorbing what it needs. Hence, I'm on a high dose of desiccated thyroid.
(I was on synthetic thyroid for 15 years before multiple myeloma diagnosis and then switched to desiccated. I actually finally found a doctor who would prescribe desiccated, but my appointment had to be postponed because, unbeknownst to me at the time, the problems I had would lead to a multiple myeloma diagnosis.)
I just keep trying to get down to the basic, basic level of what is going on -- as well as a layman can. I see a lot coming out on oxidative stress and MTHFR, hoping there will be more coming out on these in regards to multiple myeloma, remission, etc.
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