Multiple cells in this primary tumor can eventually acquire a malignant phenotype. This enables these cells to escape from the primary tumor and invade into the bloodstream or lymphatic system.
Growth Factor Receptors in Breast Cancer: Potential for Therapeutic Intervention
Subsequently, they can settle and form secondary tumors at a distant site. In breast cancer patients, it is not the primary tumor, but its metastases in other tissues that are the main cause of death. The molecular mechanisms underlying metastasis are still poorly understood and most studies have focused on features intrinsic to tumor cells. However, the tumor microenvironment also plays an important role in metastasis [ 63 ].
Prostate cancer PCa is one of the most frequently occurring malignant cancers in men, associated with a high risk of bone metastasis. To develop therapeutic treatments, it is critical to understand the mechanisms of breast cancer bone metastases. PMEPA1 may thus be a prognostic biomarker in patients suffering from breast or prostate cancer.
It has been reported that the adipokine angiopoietin-like 4 ANGPTL4 can enable human breast cancer cells to form lung metastasis by disrupting capillary vascular endothelial cell junctions [ 73 ]. Secretion of ANGPTL4 was found to enable estrogen receptor ER -negative breast cancer cells to extravasate into lung tissue and to seed micrometastases [ 73 ]. LncRNAs can regulate many important cancer-associated phenotypes, including proliferation, apoptosis, or cell migration, through their interactions with DNA, chromatin, signaling and regulatory proteins, and a variety of cellular RNA species [ 74 , 75 ].
Multiple cancer-associated lncRNAs have been identified as a new class of players regulating cancer invasion and metastases [ 76 , 77 ]. Recently, Yuan et al. LncRNAs also mediate cancer metastasis through chromatin deregulation. By a high-density Affymetrix Genechip platform from prostate cancer patients, the prostate cancer lncRNA second chromosome locus associated with prostate-1 SChLAP1 was identified as the highest-ranked overexpressed gene, associated with poor prognosis and metastatic progression [ 88 ].
In summary, these RNAs could be new cancer diagnostic and therapeutic targets. SB, Ki, and LY , and peptide aptamers e. Targeting of receptor kinase activity has been another successful therapeutic strategy. Another class of therapeutics is formed by peptides, which have a high specificity to bind targets in vivo and have relatively few off-target side effects compared with other small molecules [ , ].
In addition, Ying et al. However, development of treatments that can specifically stop or slow down the growth of primary tumors and the ever-emerging problem of metastasis is urgently needed. Clinical trials with several of these agents are currently in progress. Some drugs have reached Phase III clinical trials for a number of disease applications, particularly cancer progression and metastasis. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis.
This provides a new potential strategy for cancer therapy, i.
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Obviously, possible side effects of these strategies in normal tissues need to be carefully considered. With the current advances in DNA sequencing and transcriptional and proteomic profiling, it is likely that genomic, transcriptional and proteomic profiles will be determined within clinical trials in the future.
Blood-based tumor cell-derived material, such as circulating tumor cells CTCs , cell-free tumor DNA, and tumor-derived secreted micro-vesicles termed exosomes , can be isolated and analyzed from patients before and during clinic treatment [ — ]. Oxford University Press is a department of the University of Oxford.
It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. Institutes of Biology and Medical Science. Oxford Academic. Google Scholar. Li Ling. Hans van Dam. Fangfang Zhou. Correspondence address. It may be helpful to download and print our Questions to Ask Your Doctor card on metastatic breast cancer and take it with you to your next doctor appointment.
There's plenty of space to write down the answers to these questions, which you can refer to later. You can also download other Questions to Ask Your Doctor cards on many different breast cancer topics. These cards are a nice tool for people recently diagnosed with metastatic breast cancer, who may be too overwhelmed to know where to begin to gather information.
If you have metastatic breast cancer, talk with your health care provider before getting a seasonal flu shot to make sure it's safe for you. Find more information from the CDC about the seasonal flu. Komen Perspectives. Learn More. Therefore, some information may be out of date at this time. Facts for Life: Metastatic Breast Cancer. Donate Now Fundraise. Treatments for Metastatic Breast Cancer What is metastatic breast cancer? When can metastatic breast cancer occur? The risk of metastatic breast cancer It's not your fault you have metastatic breast cancer. It depends greatly on: The biology of the tumor characteristics of the cancer cells The stage at the time of the original diagnosis The treatments for the original cancer trying to prevent breast cancer recurrence Treatment As hard as it is to hear, metastatic breast cancer cannot be cured today.
Your treatment plan is guided by many factors, including: The biology of the tumor characteristics of the cancer cells Where the cancer has spread Your symptoms Past breast cancer treatments If the cancer is hormone receptor-positive , the first treatment is hormone therapy. Quality of life Talking about quality of life issues with your health care providers and your family can help you decide what treatments are best for you.
Treatment guidelines Although the exact treatment for metastatic breast cancer varies from person to person, guidelines help ensure high-quality care. Prognosis Modern treatments continue to improve survival for most people diagnosed with metastatic breast cancer. Monitoring metastatic breast cancer Tumors often become resistant stop responding to drugs used to treat metastatic breast cancer.
Drug resistance Some metastatic breast cancer cells need specific proteins or cell pathways to grow. You usually start a drug therapy and see whether: It controls the growth of the cancer The side effects can be managed If the treatment is working and the side effects aren't too bad at the time of restaging, the treatment is typically continued.
Blood tests for tumor markers In some cases, blood tests for tumor markers may be used to help monitor metastatic breast cancer. There is no test score that means the tumor has spread the cancer has gotten worse. Hormone therapy Hormone therapy is usually the first treatment for hormone receptor-positive metastatic breast cancers.
Hormone therapy for premenopausal women For premenopausal women with metastatic breast cancer, hormone therapy almost always begins with ovarian suppression. Hormone therapy for postmenopausal women After menopause, hormone therapy for women with metastatic breast cancer can be an aromatase inhibitor, tamoxifen or another anti-estrogen drug such as fulvestrant. When hormone therapy stops working At some point, even though it may be years away, hormone therapy almost always stops working. Abemaciclib, palbociclib and ribociclib are pills. In some cases, it can cause liver problems.
Your liver function will be checked before treatment begins and throughout your treatment. Palbociclib Some possible side effects include low white blood cell counts, low red blood cell counts anemia , fatigue, nausea, mouth sores, hair thinning, diarrhea and in rare cases, blood clots. Ribociclib Some possible side effects include low white blood cell counts, nausea, fatigue, diarrhea, hair loss, vomiting, constipation, headache and back pain. In rare cases, it can cause changes on an EKG electrocardiogram. An EKG gives information on the electrical activity of the heart.
You will get an EKG before treatment begins and throughout your treatment to check for any changes. Everolimus is a pill. Side effects of everolimus Some possible side effects of everolimus include mouth ulcers, infections, rash, fatigue, diarrhea, decreased appetite and in rare cases, lung problems [ ]. Alpelisib is a pill. Side effects of alpelisib Some possible side effects of alpelisib include high blood sugar, diarrhea, nausea, decreased appetite, rash, vomiting, fatigue and hair loss [ 81,83 ]. Trastuzumab is only used to treat HER2-positive breast cancers. Trastuzumab is given by vein through an IV or by injection.
Side effects and risks of trastuzumab Trastuzumab has fewer and different side effects than chemotherapy. Biosimilar trastuzumab Some drugs are made from biological products biologics such as antibodies or proteins. A biosimilar drug may cost less than the original drug.
FDA approval of biosimilar drugs To be approved by the U. Food and Drug Administration FDA , the biosimilar drug must work the same way as the original drug and it must have the same [ 23 ]: Safety when used alone or in combination with other treatments Effectiveness when used alone or in combination with other treatments The side effects of the biosimilar drug cannot be different from those of the original drug.
Biosimilar drugs for breast cancer treatment — biosimilar forms of trastuzumab At this time, the FDA-approved biosimilar drugs for breast cancer treatment are all biosimilar forms of trastuzumab. They can be used to treat early and metastatic HER2-positive breast cancers: Trastuzumab-anns Kanjinti Trastuzumab-dkst Ogivri Trastuzumab-dttb Ontruzant Trastuzumab-pkrb Herzuma Trastuzumab-qyyp Trazimera Other biosimilar drugs for breast cancer are under study. Biosimilar drugs used to treat side effects of breast cancer treatment Some drugs used to treat side effects of chemotherapy and other breast cancer treatments have biosimilar forms.
Pertuzumab Perjeta Pertuzumab Perjeta is a specially made antibody that targets HER2-positive cancer cells, but in a different way than trastuzumab. Pertuzumab is given by vein through an IV. Side effects of pertuzumab Some possible side effects of pertuzumab include diarrhea, rash, vomiting, headache and dry skin [ ]. Ado-trastuzumab emtansine is given by vein through an IV.
Side effects of ado-trastuzumab emtansine Some possible side effects of ado-trastuzumab emtansine include nausea, fatigue, muscle and joint pain, low platelet counts, headache and constipation [ 27 ]. Lapatinib Tykerb Lapatinib Tykerb is a tyrosine-kinase inhibitor. These drugs can block tyrosine-kinase enzymes at many points along the cancer growth pathway.
Lapatinib is a pill. Lapatinib combined with chemotherapy Compared to chemotherapy alone, chemotherapy combined with lapatinib may give women with HER2-positive metastatic breast cancer more time before the cancer spreads [ ]. Lapatinib combined with hormone therapy Compared to use of the aromatase inhibitor letrozole alone, letrozole combined with lapatinib may give women with HER2-positive metastatic breast cancer more time before the cancer spreads [ ]. Lapatinib and brain metastases Many therapies cannot pass through the blood to the brain called the blood-brain barrier to treat breast cancer that has spread to the brain.
Side effects of lapatinib Some possible side effects of lapatinib include diarrhea, nausea, vomiting, rash and fatigue [ ,34 ]. Olaparib and talazoparib are FDA-approved for breast cancer treatment. Olaparib is a pill. Side effects of olaparib Some possible side effects of olaparib include low red blood cell counts anemia , nausea, vomiting, fatigue and low white blood cell counts [ 38 ]. Talazoparib is a pill.
Side effects of talazoparib Some possible side effects of talazoparib include fatigue, low red blood cell counts anemia , nausea and vomiting, headache and diarrhea [ 40 ]. Immunotherapy Atezolizumab Tecentriq is an immunotherapy drug. Researchers are studying how to identify the best biomarkers for immunotherapy.
Why the Epidermal Growth Factor Receptor? The Rationale for Cancer Therapy
Atezolizumab Tecentriq Atezolizumab Tecentriq is a checkpoint inhibitor immunotherapy drug used to treat some PD-L1-positive breast cancers. Other immunotherapy drugs are also under study. Side effects of atezolizumab Atezolizumab increases the risk of diabetes, thyroid problems, lung inflammation and colitis inflammation of the intestines [ 41 ].
Questions for your provider. Where in my body has the breast cancer spread? What is my prognosis with treatment? Will you do a biopsy of the tumor? What are the hormone receptor status and HER2 status of my cancer? How do these affect my treatment options? Should my tumor be tested for PD-L1 status? What are my treatment options? What are the pros and cons of each option? Which do you recommend for me and why? Are there clinical trials I can join?
If so, how do I learn more? How long do I have to make treatment decisions? Should I get a second opinion? How do I do that? How will treatment affect my quality of life? In this review the molecular mechanisms that may contribute to the highly metastatic phenotype of prostate cancer are discussed. Proangiogenic factors such as vascular endothelial growth factor VEGF have been shown to not only aid in the metastatic capabilities of prostate cancer but also encourage the colonization and growth of prostate tumour cells in the skeleton.
The importance of VEGF in the complex process of prostate cancer dissemination to the skeleton is discussed, including its role in the development of the bone premetastatic niche, metastatic tumour cell recognition of bone, and bone remodeling. The expression of VEGF has also been shown to be upregulated in prostate cancer and is associated with clinical stage, Gleason score, tumour stage, progression, metastasis, and survival. Due to the multifaceted effect VEGF has on tumour angiogenesis, tumour cell proliferation, and bone destruction, therapies targeting the VEGF pathways have shown promising clinical application and are being investigated in clinical trials.
Once cancer metastasizes to bone and the vertebral column, patients often experience intractable pain and neurological deficit due to pathological fractures, spinal instability, and metastatic epidural spinal cord compression. The neurological sequelae include sensory disturbance, motor weakness, paralysis, and incontinence, leading to decreased function, inability to ambulate and impaired quality of life [ 5 ].
Treatment options include radiotherapy, hormonal therapy, chemotherapeutic agents such as docetaxel, cabazitaxel, sipuleucel-T and abiraterone acetate, and decompression and stabilization surgery [ 6 , 7 ]. These modalities may be able to extend survival rates but are all predominantly palliative, with median survival time limited from one to two years from the onset of metastases [ 5 , 6 ].
Despite the clinical implication and high incidence of spinal metastasis, the molecular mechanisms behind prostate cancer metastasis to bone and the spine are not well understood. Vascular endothelial growth factor VEGF is well known to be potent stimulator of angiogenesis in both physiological and pathological conditions and is highly expressed in most solid tumours, including prostate cancer. This review discusses the role of VEGF in tumour angiogenesis and bone destruction in metastatic prostate cancer to the spine.
Upon specific VEGF binding, the three VEGF receptors induce receptor dimerization and autophosphorylation leading to downstream signaling via a number of secondary messengers including several protein kinases and phosphatases that support a proangiogenic phenotype [ 10 — 12 ]. VEGF receptor binding. Hormones such as androgens upregulate stromal cell and malignant cell VEGF production and angiogenesis, enhancing prostate cancer growth [ 16 — 18 ]. As such, hormone withdrawal has been shown to inhibit VEGF expression as well as angiogenesis in prostate cancer patients while inducing apoptosis in these cells [ 19 ].
Angiogenesis is the growth and development of new blood vessels and is necessary to supply nutrients and maintain homeostasis in the tissues of the body [ 12 ]. Normal angiogenesis is tightly regulated by inducers and inhibitors of endothelial growth and is established from preexisting vessels, which develop ordered and predictable vasculature [ 26 ]. The actions of VEGF affect numerous cell types, thus enabling a multifaceted response.
Initial activation of VEGF promotes the secretion of proteolytic enzymes to degrade the basement membrane and extracellular matrix whilst also aiding in the proliferation and migration of endothelial cells to form immature vasculature [ 13 , 26 ]. VEGF also maintains newly formed vessels by inducing the expression of Bcl-2 and A1 anti-apoptotic proteins that promote cell survival, whilst activating colony formation by attracting mature subsets of granulocyte macrophage progenitor cells [ 27 , 28 ]. Hypoxic conditions activate the uptake of VEGF and other growth factors and induce the growth of neovasculature, allowing the tumour cells to gain access to oxygen and nutrients [ 26 , 29 — 31 ].
What is metastatic breast cancer?
Indeed, the induction of angiogenesis has been shown to correlate with the invasive properties of tumours and is associated with poor prognosis [ 32 ]. Along with tumour vascularization, activation of genes governing the disruption of cell to cell adhesion and cell motility enables proliferation of primary tumour cells as well as allowing detached cells to disseminate throughout the circulatory system [ 28 ]. In benign prostate glands, VEGF expression is mainly confined to the basal cell layer and has weak levels of VEGF binding, while in prostate tumours VEGF is upregulated and found beyond this layer, including neoplastic secretory cells [ 33 ].
During the normal development of long bones and vertebrae or bone repair, growth and remodeling of bone formation occurs through osteogenesis [ 34 ]. A balanced state is created through the continuous and integrated processes of bone formation and deposition by osteoblasts and bone and mineralized matrix resorption by proteolytic enzymes and hydrochloric acid secreted by osteoclasts, derived from the haematopoietic stem cells of the bone marrow [ 35 , 36 ].
VEGF is expressed by osteoblasts and has autocrine and paracrine effects including chemotactic migration, proliferation, and differentiation of osteoblasts, as well as stimulating the formation, survival, and resorptive activity of osteoclasts. It is essential for normal angiogenesis and appropriate bone repair and mineralization in response to bone injury [ 37 ].
In vivo, absence of VEGF leads to impaired blood vessel invasion, cartilage remodeling, and skeletal growth [ 38 — 40 ]. Blood vessels serve as a way of transporting circulating osteoblasts [ 41 ] and osteoclast precursors [ 42 ] to sites undergoing active remodelling [ 43 ]. Cancer metastases to bone cause alterations in normal bone metabolism and the balance between osteoclasts and osteoblasts in favour of one or the other, resulting in destructive lytic or sclerotic lesions, or a combination of both [ 44 ].
Osteoclasts are primarily responsible for tumour induced bone destruction, and during the resorption of the bone matrix, embedded growth factors are released that produce a permissive microenvironment and further promote tumour growth [ 30 , 45 ]. Of note, in human prostate cancer, bone metastases generally favour an osteoblastic phenotype, in contrast to other metastases such as those from renal cell carcinoma, which are often lytic [ 46 , 47 ].
The spread of prostate cancer metastasis to bone is a complex process involving tumour cell migration from the primary tumour site, dissemination through the vascular system, extravasation, and finally establishment, growth, and invasion at the secondary bone site [ 4 ]. In a clinical trial of patients with metastatic prostate cancer, bone metastases were noted in Prior to the attachment of these cancer cells to bone, it is thought that a premetastatic niche may be created by nonmalignant bone marrow-derived cells that are stimulated by tumour-secreted proteins, which in combination with various bone-enriched growth factors, cytokines, proteases, and components of the extracellular matrix such as a high extracellular calcium concentration support the colonization and growth of prostate cancer cells in bone [ 49 — 51 ].
The actions of VEGF are thought to assist in tumour cell recognition of bone and encourage nesting of the tumour cells in bone [ 52 ].
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Prior to attachment, VEGF via VEGFR2 modulates the migratory responses of tumour cells encouraging adhesion molecules such as fibronectin and bone sialoprotein within the extracellular matrix [ 53 ]. Additionally, VEGF and its cognate receptors may be able to regulate integrin activity, promoting recognition of the bone matrix [ 32 ]. Various tumour-expressed growth factors, endothelial markers, and cytokines attract and activate osteoclasts, which in turn disrupt the bone balance through overstimulation and discharge of bone-derived growth factors Figure 2.
Other factors which affect the progression of prostate cancer to bone are Dickkopf-1 DKK-1 , sclerostin, and Wnt signalling. Upregulation of DKK-1 and sclerostin enhances osteoclastic activity by suppressing Wnt signaling and is thought to be able to inhibit the advancement of bone cancer metastases [ 54 , 55 ]. Whilst DKK-1 levels in patients with bone metastases decrease, Wnt levels rise [ 56 ].
This increase of Wnt signalling promotes osteoblast and inhibits osteoclast differentiation, leading to an osteoblastic tumour phenotype [ 56 , 57 ]. Furthermore, in response to various hormonal, cellular, and cytokine signals, receptor activator of nuclear factor-k B ligand RANKL , induces osteoclast formation and activation [ 58 , 59 ].
These factors are deposited into the bone matrix and create a microenvironment that is favourable for cancer cells, leading to further proliferation of tumour cells and bone degradation through the secretion of osteolytic factors [ 61 ]. Tumour induced bone destruction.
In the prostate, an angiogenic switch promotes the secretion of VEGF, leading to various effects on cells, increasing the release of growth factors and activating integrin activity. In metastatic bone disease, tumour cells secrete humoral factors that stimulate osteoclastic and osteoblastic recruitment and differentiation. Once these osteoclasts begin to break down bone, growth factors are released, stimulating growth of the tumour cells.
This encourages the tumour cells to release factors that further increase bone resorption by osteoclast and stimulate bone formation through the activation of osteoblasts. Expression levels of VEGF and VEGFRs have also been shown to be elevated at the site of bone metastases in comparison to primary prostate tumours, indicating that VEGF is an important factor in metastasis development, particularly to bone [ 53 ].
Growth Factor Receptors in Breast Cancer: Potential for Therapeutic Intervention
Increased VEGF plasma levels have been shown to correlate with skeletal metastasis and poor prognosis in prostate cancer patients and VEGF expression levels in many cancer types have been shown to correlate with poorer prognosis and metastatic potential [ 62 ]. However, other studies have shown that there is no correlation between VEGF serum levels and prognosis [ 63 , 64 ].
The expression of VEGF is upregulated in prostate cancer and is associated with clinical stage, Gleason score, tumour stage, progression, metastasis and survival [ 65 — 67 ]. Many prostate cancer cell lines known to produce osteoblastic metastases highly express VEGF [ 68 ]. High expression of VEGF has been observed in human metastatic prostate cancer cell lines PC-3, Du, and line LNCaP-C4—2, where it has been shown to promote osteoblastic differentiation and activity in vitro [ 53 , 71 — 73 ]. Traditionally, androgen ablation has been the main treatment for the prevention of metastases from prostate cancer.
As prostate cancer cells are initially dependant on androgens, suppressing the levels of testosterone and dihydrotestosterone decreases the growth rate of prostate cancer cells [ 74 ]. However, after this initial response these cells can become castrate-resistant and develop a more aggressive phenotype, with increased VEGF expression and proliferative potential [ 74 , 75 ]. The commonest conventional treatments for bone metastases secondary to prostate cancer are chemotherapy, radiation, and surgery. Although chemo- and radiotherapy has the potential ability to kill rapidly dividing cancer cells, they each have their own toxic side effects and there is little survival benefit in patients with metastatic cancer [ 76 , 77 ].
Bisphosphonates such as zoledronic acid or Denosumab, a human monoclonal antibody that targets RANKL signalling, also have a therapeutic role in preventing skeletal-related events in bone metastases via inhibition of osteoclast-mediated bone resorption [ 78 ]. Patient morbidity and mortality due to local tumour recurrence, multimetastatic disease, loss of structural function of the bony skeleton destroyed by tumour, and metastatic epidural nerve or spinal cord compression remain important challenges.
Due to the multifaceted effect VEGF has on tumour angiogenesis, tumour cell proliferation, and bone destruction, antiangiogenic therapies targeting the VEGF pathways have shown promising early clinical application and are being investigated in clinical trials. Bevacizumab is currently in Phase II clinical trials in relapsed prostate cancer and is approved by the US Food and Drug Administration FDA for treatment of metastatic colorectal, renal, and breast cancer and other solid tumours [ 80 , 81 ].
Similarly, Aflibercept is another antibody which neutralizes VEGF and is currently being used in Phase II clinical trials for patients with recurrent or metastatic urothelial cancer [ 82 ]. Tyrosine kinase inhibitors act on VEGF receptors inhibiting activation following ligand binding [ 83 ]. Recently, studies have suggested that using anti-VEGF therapies such as Bevacizumab in concert with radiation therapy or chemotherapy may be able to increase the response to radiation therapy [ 86 ].
These synergistic actions have been reported in several preclinical studies and have been shown to improve the survival rates in patients with advanced cancers and decrease levels of radiation necrosis [ 86 — 88 ]. To date there have been many articles published suggesting the possible molecular mechanisms behind the propensity of prostate cancer to metastasize to bone and the vertebral column. VEGF has been implicated in many of these, including facilitating cancer cell migration to bone, induction of angiogenesis, and stimulating bone forming and resorbing cells of the bone marrow.
Further research is required to determine whether this may be translated into better disease control, decreased morbidity, higher survival rates, and improved quality of life in patients with prostate cancer.
Prostate Cancer. Published online Dec PMID: