Background

The BMP (Bone morphogenetic protein) signaling pathway plays a crucial role in various aspects of metazoan biology. From embryonic development to tissue homeostasis and disease progression, the BMP signaling exerts a profound influence on cellular processes and organismal physiology (Massagué 2012). The outcome of BMP signaling response in cancer is highly context-dependent. The regulatory cytokine BMP exerts tumor-suppressive effects that cancer cells must evade to undergo malignant evolution (Cai et al. 2012; Guo and Wang 2009; Owens et al. 2015). Paradoxically, BMP also modulates processes such as cell invasion, stemness, and modification of the microenvironment that cancer cells may exploit to their advantage (Martínez et al. 2017; Wang et al. 2019; Yan et al. 2012).

Cancer stem cells (CSCs), also known as tumor-initiating cells, are a small subpopulation of quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic tumors and later in solid malignancies (Bao et al. 2006; Chen et al. 2012; Shibue and Weinberg 2017). CSCs possess stem-like properties and contribute to tumor initiation, progression, and resistance to therapy. Their role in tumor resistance to chemotherapy and radiation treatment, as well as recurrence, has garnered significant research interest. CSCs are thought to be preserved as a small population through self-renewal, and to generate more differentiated progenies that constitute the bulk of the tumor mass (Kreso and Dick 2014). In addition to providing the driving force for tumor growth and maintenance, CSCs have been shown to be more resistant to existing anticancer therapies, consistent with their role in relapse after therapy. Accordingly, transcriptional signatures of CSCs are predictive of overall patient outcome, supporting their clinical relevance.

The expanding array of aberrant signaling pathways, including BMP, Hippo, Hedgehog, JAK/STAT, Wnt, Notch, PI3K/PTEN, and NF-κB, distinctly regulates the sustenance of cancer stem cells (CSCs) (Clara et al. 2020; Takebe et al. 2015; Yang et al. 2020). While governing normal stem cell equilibrium, these pathways often experience anomalous activation or repression in CSC contexts. The BMP antagonist COCO plays a pivotal role in modulating the reawakening of dormant metastatic breast cancers linked to CSCs in the lung, whereas BMP signaling itself exerts suppressive effects (Gao et al. 2012). YAP/TAZ activation equally emerges as significant, instigating CSC attributes, fueling proliferation, encouraging chemoresistance, and driving metastasis (Zanconato et al. 2016). The JAK/STAT pathway, a pivotal player, drives CSC-mediated metastasis and proliferation in various cancers, including colon cancer (Calon et al. 2012), glioblastoma (Sherry et al. 2009), and breast cancer (Zhou et al. 2007).

Importantly, these pathways form a complex interwoven network of signaling mediators, intricately interacting and fostering a labyrinthine cross-talk. This interconnected web underscores the significance of understanding not only each pathway’s distinct role but also their collaborative dynamics. Together, they intricately shape the landscape of CSC regulation and cancer progression.

Understanding the biology of CSCs and their interactions with the tumor microenvironment is of paramount importance in the pursuit of effective therapies for intractable tumors. The intricate functioning of the BMP signaling has been demonstrated to play a crucial role in regulating CSC self-renewal, differentiation, and the modulation of the tumor microenvironment in various cancer types (Table 1). Moreover, the influence of BMP signaling extends beyond CSCs, intricately regulating cellular migration, invasion, and metastasis across different tumors.

Table 1 The BMP family members and their functions in stemness and differentiation of various cancers
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The complex nature of BMP signaling in cancer underscores the need to comprehend its effects within the cellular context and the tumor microenvironment. Given the interplay between the tumor-suppressive and tumor-promoting aspects of BMP signaling, it is imperative to grasp the underlying mechanisms and specific molecular interactions involved. Thus, the objective of this article is to provide a concise overview that highlights the diverse roles of the BMP signaling in various types of cancers.

Basics of BMP signaling pathway

The core BMP signaling components are largely conserved across metazoans (Massagué 2012). The BMP signaling pathway comprises an extensive repertoire of ligands, with more than 20 identified members. These ligands can be classified based on their nucleotide or amino acid similarities. Among the noteworthy ligands within the pathway are BMPs 2, 4, 6, 7, 9, and 15, along with growth differentiation factors (GDFs) 5 and 9, and anti-Müllerian hormone (David and Massagué 2018) (Table 2). Initially derived from demineralized bone matrix, BMPs exhibit remarkable capacity to induce bone formation (Yang et al. 2020). These ligands belong to the transforming growth factor (TGF)-β superfamily (Derynck et al. 2021; Liu et al. 2021).

Table 2 The BMP family members and their receptors
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During embryogenesis, BMP signaling participates in key developmental events such as dorsal-ventral patterning, mesoderm and ectoderm specification, as well as organogenesis (Jia et al.

BMP signaling in lung cancer

Lung cancer is the leading cause of cancer mortality and accounts for 30% of all deaths from cancer (Jemal et al. 2010; Siegel et al. 2013). Despite advancements in medical care, the prognosis for lung cancer remains poor, with 85% of patients succumbing to the disease. BMP signaling, which is normally absent in adult lung tissue (Sountoulidis et al. 2012), becomes reactivated in lung injury as well as non-small cell lung carcinomas (NSCLC) and small cell carcinomas (Langenfeld et al. 2005). NSCLC exhibits significant overexpression of BMP2 compared to normal lung tissue and benign tumors, and depletion of BMP2 or its receptor BMPR2 has been shown to reduce cell migration and invasiveness (Wu et al. 2022).

Recent studies have shown that the BMP signaling plays a crucial role in promoting lung cancer cell growth and survival (Langenfeld et al. 2013). Downregulation of type I BMP receptors with siRNA or small molecule inhibitors (DMH1, DMH2) in lung cancer cells caused growth inhibition and cell death, while the forced expression of ID3 attenuated growth suppression and cell death caused by BMP receptor inhibitors. These findings suggest that BMP signaling is a potential therapeutic target for lung cancer treatment (Augeri et al. 2016). Furthermore, combining inhibition of BMP signaling with mitochondrial targeting agents induces AIF (apoptosis-inducing factor) caspase-independent cell death by hyperactivating AMPK, indicating the potential use of this combination as a novel therapeutic strategy for lung cancer treatment (Mondal et al. 2022). Moreover, RUNX2 could recruit histone H3K9-specific methyltransferase Suv39h1 to BMP3B (GDF10) proximal promoter and then suppress the BMP3B expression, which is regarded as a tumor growth inhibitor and a gene silenced in lung cancers (Dai et al. 2004; Tandon et al. 2012).

Taken together, these finding demonstrate that BMP signaling plays an essential role in lung cancer cell growth and survival. BMP signaling inhibitors could present a potential therapeutic target for lung cancer treatment, alone or in combination with other agents. However, further research is needed to investigate the clinical utility of targeting BMP signaling for lung cancer treatment.

BMP signaling in prostate cancer

Prostate cancer is a significant cause of male cancer-related mortality (Siegel et al. 2016). The interplay between TGF-β and BMP signaling pathways within prostate cancer is intricate, with distinct roles (Lu et al. 2017). Genetic deletions of Tgfbr2 and Bmpr2 in a Pten-null mouse model reveal that TGFβ restrains cancer progression, while BMP signaling drives advancement (Lu et al. 2017). BMP signaling interacts with pathways like WNT and PI3K/AKT, fostering cancer progression and therapy resistance (Chen et al. 2016; Lee et al. 2014a; Murillo-Garzón and Kypta 2017). BMP ligands are key subjects in research on prostate cancer stemness, migration, invasion, growth, and metastasis.

Within the intricate landscape of prostate cancer, the architects of disorder manifest as basal and ductal stem cells, wielding the potential to spark tumorigenesis and invariably contributing to the unsettling specter of tumor recurrence (Choi et al. 2008), BMP (Ren et al. 2020), PDGF (Nissen et al. 2007), and the JAK/STAT pathways (Yadav et al. 2011).

In the realm of cancer, the TGFβ pathway’s duality has been long acknowledged. Its role wavers between anti-tumor sentinel and pro-metastasis instigator, its inclination hinging upon cellular phenotype, genetic aberrations, and an array of allied factors (Massagué 2008). Similarly, mirroring TGFβ’s enigmatic behavior, BMP engagement with tumor cells showcases a dual face. While initially stifling cellular proliferation, BMP stimulation paradoxically emboldens the machinery of cell migration and invasion, as observed in compelling research (Ketolainen et al. 2010).

BMP signaling frequently intersects with other signaling pathways, sometimes acting as a facilitator of tumor metastasis. Recent investigations have unveiled intriguing insights. Notably, in the context of highly invasive breast cancers, TGFβ signaling has been found to counteract BMP-induced SMAD1/5/8 activation. This interplay leads to a substantial reduction in tumor self-seeding, as well as diminished liver and bone metastasis (Ren et al. 2020). In a related context, the interplay between BMP and SHH pathways forms a cooperative and intricate cycle that fuels the bone metastasis of prostate cancer, as observed in prior studies (Nishimori et al. 2012).In addition, the interwoven connection of BMP and NF-κB signaling pathways emerges as a pivotal driver of both oncogenesis and metastasis in esophageal squamous cell carcinoma, a revelation elucidated through research endeavors (Lau et al. 2017).

Moreover, the activation of BMP signaling within the neighboring tumor microenvironment has been found to potentiate the metastatic dissemination of tumors. Specifically, the stimulation of fibroblasts by BMP can exert diverse effects. In the context of prostate tumors, BMP stimulation of fibroblasts has been demonstrated to foster angiogenesis (Yang et al. 2008). Similarly, when mammary fibroblasts are exposed to BMP stimulation, it leads to an augmentation in tumor cell invasion. This is coupled with an escalation in the secretion of inflammatory cytokines and the remodeling of the extracellular matrix (Owens et al. 2013).

Recent investigations have illuminated the potential of systemic BMP signaling inhibition as a means to halt tumor progression and metastasis, encompassing both the tumor itself and its microenvironment. A noteworthy illustration comes from the use of DMH1, a BMP antagonist, which has exhibited promising outcomes. Treatment with DMH1 has shown the capability to curtail lung metastasis in breast cancer. Additionally, in vivo results displayed a reduction in tumor proliferation and an increase in apoptotic processes, highlighting the potential therapeutic significance of modulating BMP signaling (Owens et al. 2015).

Collectively, these investigations substantiate the multifaceted role of BMP signaling in the intricate landscape of cancer evolution and advancement. BMP signaling exhibits a dichotomy, capable of curbing tumor stemness while concurrently fostering the orchestration of organ-specific tumor metastasis (Fig. 2). The intricate interplay between BMP signaling and other prominent pathways serves as a facilitator, steering the course of tumor metastatic spread and overall progression across various cancer types. Emerging as a promising avenue for therapeutic intervention, the restraint of BMP signaling within both the tumor and its encompassing microenvironment emerges as a prospective approach in combatting the specter of future cancer metastasis.

Fig. 2
figure 2

The role of BMP signaling in various human cancers. BMP signaling exhibits context-dependent pleiotropic effects across diverse cancers. In certain cancer types (e.g., lung cancer), BMP signaling can drive tumorigenesis, whereas in others (e.g., GBM), it exerts inhibitory influence on tumor progression. Notably, within distinct tumor subtypes of DIPG and AML, BMP signaling assumes a dual role. Furthermore, the functions of BMP signaling in prostate cancer and osteosarcoma are contingent upon the cellular context, introducing variability in its impact. Created with BioRender.com

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Conclusions and perspectives

This review provides an overview of the findings from numerous studies that have investigated the function of BMP signaling in cancer stemness and differentiation. Similar to the TGFβ signaling pathway, the role of the BMP pathway in tumorigenesis is complex and varies depending on the specific cellular context, acting as either a tumor suppressor or a tumor promoter.

Understanding the precise mechanisms and the intricate crosstalk between the BMP and TGFβ signaling pathways is of great importance to unravel the complexities of tumorigenesis. While the BMP signaling has been implicated in various aspects of cancer development, including tumor growth, metastasis, and stemness (Table 1 and Fig. 2), there are still many unanswered questions. One such question pertains to the potential overlap** and distinct roles of the BMP and TGFβ pathways in different types of cancers. Further investigation is needed to elucidate the interplay and competitive effects between these two signaling pathways within tumor cells.

Importantly, the activity of BMP signaling is tightly regulated by a plethora of factors, and disrupting this delicate balance can alter the characteristics of normal cells and lead to their transformation into tumor cells (Table 1). Understanding the key factors involved in this regulatory process is crucial for comprehending the development and progression of cancer. In this regard, secreted antagonists play a significant role in the regulatory network of BMP signaling. The tumor microenvironment is enriched with various secreted factors, including BMP signaling antagonists. The concentration and activity of BMP ligands and antagonists may depend on intricate cell-to-cell communication, and it has been suggested that cancer stem cells may secrete BMP signaling antagonists as a means to inhibit the BMP pathway within the tumor microenvironment. Hence, investigating the roles of BMP ligands and antagonists within the tumor microenvironment may provide valuable insights into the regulatory networks that influence cancer development and progression.

BMP ligands introduce further layers of intricacy to the already complex regulatory landscape within different tumors. It’s noteworthy that distinct BMP ligands might execute analogous functions within a given tumor. Paradoxically, a singular BMP ligand could even yield disparate functions when situated in diverse tumor types. As a result, the influence of BMP signaling takes center stage within specific tumor contexts. Delving into the operational mechanisms of these ligands becomes imperative, as it holds the potential to elucidate the exact contribution of the BMP pathway within these specific tumor types.

Given the diverse roles of BMP signaling in cancer, there is considerable potential for the development of novel therapeutic approaches targeting these pathways. In cases where BMP signaling acts as a tumor suppressor, delivering exogenous BMP ligands to tumors using various methods, such as through the use of vaccinia viruses, may hold clinical promise and offer potential benefits to patients. Additionally, targeting BMP signaling pathway antagonists or negative regulators, such as NOG (noggin) and SMAD6, using small molecule inhibitors could effectively promote BMP signaling activity and potentially inhibit tumor growth.

Conversely, in situations where BMP signaling act as tumor promoters, interventions at different levels could be considered. Direct delivery of inhibitors, such as antisense oligonucleotides, specifically targeting BMP ligand production within the tumor, could potentially offer a means to prolong patient survival. Furthermore, inhibiting ligand-receptor interactions using antibodies against BMP ligands or BMP receptors, as well as employing small molecule inhibitors that target BMP receptor kinases, like LDN-193,189, could provide alternative and potentially more effective therapeutic approaches for blocking BMP signaling in tumors.

Lastly, since BMP ligands and antagonists are secreted proteins, the measurement of their concentrations in a patient’s blood or specific tissues may have diagnostic value and could aid in assessing the level of tumorigenesis. Monitoring the levels of these signaling molecules may offer valuable insights into disease progression and guide treatment decisions.

In conclusion, the comprehensive understanding of BMP signaling in cancer is a complex and evolving field. The intricate interplay between BMP, TGFβ and other signaling pathways, the balance of BMP ligands and antagonists in the tumor microenvironment, and the potential for targeted therapeutic interventions make this an area of great interest for future research and the development of personalized cancer therapies.