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Role of TGF-β in breast cancer bone metastases.

Chiechi A, Waning DL, Stayrook KR, Buijs JT, Guise TA, Mohammad KS - Adv Biosci Biotechnol (2013)

Bottom Line: TGF-β, in turn, stimulates bone metastatic tumor cells to secrete factors that further drive osteolytic bone destruction adjacent to the tumor.Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression.Blocking the TGF-β signaling pathway to interrupt this vicious cycle between breast cancer and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Internal Medicine, Indiana University, Indianapolis, USA.

ABSTRACT
Breast cancer is the most prevalent cancer among females worldwide leading to approximately 350,000 deaths each year. It has long been known that cancers preferentially metastasize to particular organs, and bone metastases occur in ~70% of patients with advanced breast cancer. Breast cancer bone metastases are predominantly osteolytic and accompanied by increased fracture risk, pain, nerve compression and hypercalcemia, causing severe morbidity. In the bone matrix, transforming growth factor-β (TGF-β) is one of the most abundant growth factors, which is released in active form upon tumor-induced osteoclastic bone resorption. TGF-β, in turn, stimulates bone metastatic tumor cells to secrete factors that further drive osteolytic bone destruction adjacent to the tumor. Thus, TGF-β is a crucial factor responsible for driving the feed-forward vicious cycle of cancer growth in bone. Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression. Blocking the TGF-β signaling pathway to interrupt this vicious cycle between breast cancer and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis. This review will describe the role of TGF-β in breast cancer and bone metastasis, and pre-clinical and clinical data will be evaluated for the potential use of TGF-β inhibitors in clinical practice to treat breast cancer bone metastases.

No MeSH data available.


Related in: MedlinePlus

Breast cancer bone metastases. When active TGF-β is released from the bone matrix upon bone resorption by osteoclasts it acts on breast cancer cells to stimulate the production of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), connective tissue growth factor (CTGF) and interleukin-(IL) 6 and −11. These factors increase the RANKL/OPG expression ratio in osteoblasts, which bind to the RANK receptors expressed on osteoclasts and activate osteoclastogenesis. TGF-β can directly stimulate osteoclast activity and inhibiting osteoblast differentiation thus, TGF-β can stimulate tumor growth.
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Figure 1: Breast cancer bone metastases. When active TGF-β is released from the bone matrix upon bone resorption by osteoclasts it acts on breast cancer cells to stimulate the production of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), connective tissue growth factor (CTGF) and interleukin-(IL) 6 and −11. These factors increase the RANKL/OPG expression ratio in osteoblasts, which bind to the RANK receptors expressed on osteoclasts and activate osteoclastogenesis. TGF-β can directly stimulate osteoclast activity and inhibiting osteoblast differentiation thus, TGF-β can stimulate tumor growth.

Mentions: TGF-β is able to promote and aggravate bone metastases through specific gene inductions. The TGF-β-Smad signaling pathway induces the production of proosteolytic factors, such as interleukin 11 (IL11), connective tissue growth factor (CTGF), matrix metalloproteinase-1 (MMP-1), CXCR4 and parathyroid hormone-related protein (PTHrP) [107]. PTHrP is widely expressed in many tissues and shares sequence homology with PTH. It is known to be expressed in most primary breast cancers tumors as well as in bone metastases. PTHrP plays a major role in the development of the osteolytic lesions and is considered to be responsible for the humoral hypercalcemia of malignancy [108]. In a large prospective study it was demonstrated that PTHrP expression in primary breast cancer was significantly associated with less bone metastases [109–111]. This study could give the explanation of the observed increase in PTHrP expression in breast cancer bone metastases, which is, it is the release of TGF-β from the bone matrix after bone resorption is what causes the cancer cells to express PTHrP and not the tumor cells that colonized the bone intrinsically express higher PTHrP level. In mouse model of bone metastases, it was first demonstrated by Yin et al. that blocking TGF-β signaling by stably transfecting a dominant negative TβRII (DNTβRII), in MDA-231 breast cancer cells, inhibited TGF-β-induced expression of PTHrP production in tumor cells. This is in return suppressed the development of osteolytic lesion area [11]. In another study, I was reported that stable overexpression of dominant-negative Smad 2, 3 and 4 in MDA-231 breast cancer cells resulted in decrease in PTHrP production [112]. TGF-β-induced PTHrP stimulated the production of RANKL and downregulating OPG thus inducing osteoclast differentiation and activation and promoting bone metastases [113]. IL-11 and CTGF both is pro-osteolytic gene. IL-11 stimulates the expression of osteoclastogenic factors RANKL and GM-CSF in osteoblasts and stimulating bone resorption. CTGF is an extracellular mediator of invasion and angiogenesis. Both, IL-11 and CTGF are shown to be directly regulated by TGF-β via the canonical TGF-β/Smad pathway in metastatic cells [10] (Figure 1).


Role of TGF-β in breast cancer bone metastases.

Chiechi A, Waning DL, Stayrook KR, Buijs JT, Guise TA, Mohammad KS - Adv Biosci Biotechnol (2013)

Breast cancer bone metastases. When active TGF-β is released from the bone matrix upon bone resorption by osteoclasts it acts on breast cancer cells to stimulate the production of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), connective tissue growth factor (CTGF) and interleukin-(IL) 6 and −11. These factors increase the RANKL/OPG expression ratio in osteoblasts, which bind to the RANK receptors expressed on osteoclasts and activate osteoclastogenesis. TGF-β can directly stimulate osteoclast activity and inhibiting osteoblast differentiation thus, TGF-β can stimulate tumor growth.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928102&req=5

Figure 1: Breast cancer bone metastases. When active TGF-β is released from the bone matrix upon bone resorption by osteoclasts it acts on breast cancer cells to stimulate the production of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), connective tissue growth factor (CTGF) and interleukin-(IL) 6 and −11. These factors increase the RANKL/OPG expression ratio in osteoblasts, which bind to the RANK receptors expressed on osteoclasts and activate osteoclastogenesis. TGF-β can directly stimulate osteoclast activity and inhibiting osteoblast differentiation thus, TGF-β can stimulate tumor growth.
Mentions: TGF-β is able to promote and aggravate bone metastases through specific gene inductions. The TGF-β-Smad signaling pathway induces the production of proosteolytic factors, such as interleukin 11 (IL11), connective tissue growth factor (CTGF), matrix metalloproteinase-1 (MMP-1), CXCR4 and parathyroid hormone-related protein (PTHrP) [107]. PTHrP is widely expressed in many tissues and shares sequence homology with PTH. It is known to be expressed in most primary breast cancers tumors as well as in bone metastases. PTHrP plays a major role in the development of the osteolytic lesions and is considered to be responsible for the humoral hypercalcemia of malignancy [108]. In a large prospective study it was demonstrated that PTHrP expression in primary breast cancer was significantly associated with less bone metastases [109–111]. This study could give the explanation of the observed increase in PTHrP expression in breast cancer bone metastases, which is, it is the release of TGF-β from the bone matrix after bone resorption is what causes the cancer cells to express PTHrP and not the tumor cells that colonized the bone intrinsically express higher PTHrP level. In mouse model of bone metastases, it was first demonstrated by Yin et al. that blocking TGF-β signaling by stably transfecting a dominant negative TβRII (DNTβRII), in MDA-231 breast cancer cells, inhibited TGF-β-induced expression of PTHrP production in tumor cells. This is in return suppressed the development of osteolytic lesion area [11]. In another study, I was reported that stable overexpression of dominant-negative Smad 2, 3 and 4 in MDA-231 breast cancer cells resulted in decrease in PTHrP production [112]. TGF-β-induced PTHrP stimulated the production of RANKL and downregulating OPG thus inducing osteoclast differentiation and activation and promoting bone metastases [113]. IL-11 and CTGF both is pro-osteolytic gene. IL-11 stimulates the expression of osteoclastogenic factors RANKL and GM-CSF in osteoblasts and stimulating bone resorption. CTGF is an extracellular mediator of invasion and angiogenesis. Both, IL-11 and CTGF are shown to be directly regulated by TGF-β via the canonical TGF-β/Smad pathway in metastatic cells [10] (Figure 1).

Bottom Line: TGF-β, in turn, stimulates bone metastatic tumor cells to secrete factors that further drive osteolytic bone destruction adjacent to the tumor.Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression.Blocking the TGF-β signaling pathway to interrupt this vicious cycle between breast cancer and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Internal Medicine, Indiana University, Indianapolis, USA.

ABSTRACT
Breast cancer is the most prevalent cancer among females worldwide leading to approximately 350,000 deaths each year. It has long been known that cancers preferentially metastasize to particular organs, and bone metastases occur in ~70% of patients with advanced breast cancer. Breast cancer bone metastases are predominantly osteolytic and accompanied by increased fracture risk, pain, nerve compression and hypercalcemia, causing severe morbidity. In the bone matrix, transforming growth factor-β (TGF-β) is one of the most abundant growth factors, which is released in active form upon tumor-induced osteoclastic bone resorption. TGF-β, in turn, stimulates bone metastatic tumor cells to secrete factors that further drive osteolytic bone destruction adjacent to the tumor. Thus, TGF-β is a crucial factor responsible for driving the feed-forward vicious cycle of cancer growth in bone. Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression. Blocking the TGF-β signaling pathway to interrupt this vicious cycle between breast cancer and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis. This review will describe the role of TGF-β in breast cancer and bone metastasis, and pre-clinical and clinical data will be evaluated for the potential use of TGF-β inhibitors in clinical practice to treat breast cancer bone metastases.

No MeSH data available.


Related in: MedlinePlus