Naheed Ali, MD, PhD
The risk of bone metastasis is very high in patients with advanced breast cancer. Despite improvements in primary breast cancer treatment, metastatic bone disease is still incurable and has a poor relative survival rate. Therefore, new therapeutic strategies are needed to increase these patients' chances of survival and treatment success. One of the most common places for breast cancer to metastasize is the bone. When disseminated tumor cells reach the bone, they may enter a dormant state and remain dormant until they start to grow again, leading to overt metastasis. At this point, the disease is distinguished by excessive osteolysis caused by osteoclasts. Breast cancer bone metastasis is initiated and progresses as a result of the osteoclasts, osteoblasts, and endothelial cells of the bone microenvironment.
Direct cell-to-cell contact and soluble factors regulate crosstalk between disseminated bone cells and breast cancer cells. Because both bone cells and cancer cells produce ILs and matching receptors are expressed, interleukins (ILs) have been identified as key regulators in this complex signaling network. ILs regulate bone cell differentiation and function, with several ILs being reported to be pro-osteoclastogenic. The presence of ILs (e.g., in serum) has consistently been linked to a poor prognosis in breast cancer. We discuss the function of the most extensively studied review which discusses the role of ILs in the development of breast carcinoma bone metastasis and their ability as therapeutic targets for halting bone metastasis.
When tumor cells proliferate in bone, they disrupt the delicately regulated bone remodeling cycle by secreting substances like interleukins (ILs) and parathyroid hormone-related protein (PTHrP), which prompt osteoblasts to produce more receptor activator of NF- κB ligand (RANKL). RANKL promotes the differentiation of osteoclast precursors into mature, bone-resorbing osteoclasts by binding to its cognate receptor RANK on osteoclasts. Transforming growth factors (TGF-), for example, are released from the resorbed bone matrix as a result of increased osteoclastogenesis and enhanced bone resorption [3,4]. As a result, the vicious cycle of bone metastasis begins, emphasizing the significance of bone cell-tumor cell crosstalk in the progression of the disease.
Given that the disease cannot be reversed once it has spread to the bone, it is necessary to develop treatment strategies that focus on the initial stages of disease development, including tumor cell colonization and dormancy escape, in order to improve the prognosis and treatment outcomes for patients with bone metastasis of breast cancer. Disseminated tumour cells (DTCs) come into contact with a diverse microenvironment in the bone upon their arrival that is made up of cellular and molecular entities very different from the primary tumor's original environment. In his "seed and soil" theory, Steven Paget stated that DTCs ("seeds") must come into contact with a fertile environment ("soil") that is conducive to their growth at secondary sites as early as 1889 [5,6]. Due to the continuous accessibility of growth-promoting factors that are secreted during bone remodeling, Paget proposed that bone provides such a soil for DTCs. The term "metastatic niche" refers to specialized environments that regulate dormancy of tumor cells and development of metastases at distant sites as a result of research that has improved our understanding of the metastatic process over the past few years.
The endosteal niche in bone, which contains osteoblasts, osteoclasts, and fibroblasts, is made up of hematopoietic stem cells, vascular endothelial cells, and osteoblasts [7,8]. Additionally, increasing evidence suggests that a number of other cell types, such as adipocytes, immune cells, osteocytes and megakaryocytes, mediate metastatic growth in bone [8–12]. Recent studies also indicate that tumor cells preferentially colonize regions where they overlap, suggesting that it is still impossible to completely separate these niches [13]. Solvable factors in the metastatic niche mediate cellular communication in addition to direct cell-cell contact.
Interleukins (ILs), immunomodulatory properties cytokines, are regarded in this context as important regulators of the bone cell-DTC crosstalk. The role of ILs during the early phases of breast cancer bone metastasis, including the enlistment of circulating tumor cells to the metastatic site, maintenance and escape from dormancy and colonization of the metastatic site, is not fully described in the current literature, though. Here, we discuss and review the role of the four most well-validated ILs (IL-1, IL-6, IL-8, and IL-11) in the early stages of breast cancer bone metastasis when bone cells and cancer cells are communicating with one another.
Interleukins were found to be small, secreted signaling proteins that facilitate leukocyte communication among immune cells (reviewed in great detail in [14]). In fact, immune cells produce the majority of ILs [15]. However, it is now known that a number of other cell types, such as bone cells and tumor cells, can produce ILs and can react to both paracrine and autocrine IL-signaling [16–20]. ILs alter a number of physiological cell processes, such as proliferation, apoptosis and differentiation, by attaching to their cognate cell surface receptor. There have been 38 ILs identified overall since the discovery of IL-1 in 1977, each with unique biological and signaling characteristics (Table 1). Although there are many different classification schemes, briefly, ILs are divided into families based on similarity in biological function, sequence, and/or receptor chain [21,22].
The cytokine receptor families of type I and type II, as well as the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR), are examples of receptors [23]. JAK/STAT, also known as Janus kinase, is a signal transducer and transcription activator and other intracellular signalling cascades, including mitogen-activated protein kinase (MAPK),phosphoinositide 3-kinase (PI3-K) and extracellular signal-regulated kinase (ERK), are involved in signaling via type I and type II receptors, such as IL-6 or IL-11, for example [23]. TNF receptor associated factor 6 (TRAF6), c-Jun N-terminal kinase (JNK), nuclear factor-kappa B (NFkB), and p38 are involved in the signaling that occurs downstream of the IL-1R/TLR axis [23].
It should be noted that IL-8 belongs to the CXC-motive chemokine family, whereas IL-1, IL-11 and IL-6 are cytokines that are members of the interleukin family [24]. As a result, it is also known as CXCL-8 and communicates with cells through the chemokine receptors CXCR1 and CXCR2 (Table 1) [24]. Although IL-8 is technically more of a chemokine than an interleukin, we decided to include it in this review due to its significant role in the initiation and development of breast cancer bone metastasis.
Resorption of bone by osteoclasts and subsequent development of new bone by osteoblasts maintain the integrity of the skeleton in a balanced manner [25]. The RANKL/RANK/osteoprotegerin (OPG)—axis and signaling of canonical Wnt are important signaling pathways that control bone remodeling. The hormones parathyroid hormone (PTH), growth hormones and vitamin D all function as endocrine and paracrine regulators of bone remodeling [26]. Both osteoblasts and osteoclasts have been shown to be affected by ILs in terms of function and maturation [27–29]. Both cell types express the appropriate receptors and secrete ILs [18,30-33]. As a result, autocrine and paracrine signaling as well as IL-mediated crosstalk between osteoclasts and osteoblasts contribute to the regulation of bone remodeling.
It is known that the majority of ILs have pro-osteoclastogenic effects, either directly or indirectly, on osteoclast differentiation, maturation and function [34,35]. Osteoclastogenesis is induced in vitro by ILs (such as IL-6 and IL-11), which are produced by bone marrow stromal cells [28]. For instance, IL-6 can cause osteolysis by interfering with the PGE2/COX-2 signaling cascade, which changes the RANK/RANKL/OPG ratio to favor enhanced osteoclastogenesis [36]. However, through JAK1/STAT3 signaling, ILs can also stimulate osteoclastogenesis independently of RANKL [37]. The effects on osteoblasts vary depending on the interleukin as well as the study models used (human vs. mouse osteoblasts, dose of stimulation and time), whereas the published effects of ILon osteoclasts primarily report a pro-osteoclastic role [17,18,33,36,38,39]. For instance, IL-1 has been shown to affect osteoblast differentiation in a biphasic manner in accordance with the timing of stimulation [38].
Importantly, it is believed that stromal cells in the bone marrow, such as osteoblasts and fibroblasts, produce a large number of ILs in response to substances released during bone resorption (such as TGF-), which may promote bone resorption [40,41] and create a feedback loop. In fact, upregulation of ILs has been linked to a number of skeletal diseases, such as osteoporosis, rheumatoid arthritis, and cancer-induced bone disease [33,42-44].
Osteolytic bone metastases from breast cancer are those that are primarily brought on by excessive bone destruction mediated by osteoclast [45]. Given that ILs play an osteoclast-promoting role in physiological bone remodeling, it is clear that they play a part in breast cancer bone metastasis. According to reports, patients with breast cancer bone metastases have higher serum levels of IL-11 and IL-8 than those with primary breast cancer. Additionally, compared to patients with only one confirmed metastatic site, serum IL-6 levels were greater in those with several sites of breast cancer metastases. [48,49]. Patients with high levels of IL-6 also had significantly lower survival rates than those with low levels [48]. Additionally, analysis of tissue samples from stage II/III breast cancer patients showed a correlation between IL-1 expression in tumor cells and bone metastases of the disease [50]. Additionally, breast cancer cells' expression of IL-1, IL-6, IL-8, or IL-11 has been linked to both their propensity for metastasis and aggressive behavior [20,37,51–53]. Additionally, mice with metastatic tumors had elevated levels of IL-1 and IL-6 in their serum [9].