• Integrins
• Targeted therapy
• Tumor

• Humans
• Integrins/metabolism
• Integrins/antagonists & inhibitors
• Neoplasms/metabolism
• Neoplasms/drug therapy
• Neoplasms/pathology
• Signal Transduction
• Molecular Targeted Therapy
• Neovascularization, Pathologic/metabolism
• Animals
• Cell Communication
• Extracellular Matrix/metabolism

• Breast cancer
• Integrin β1
• Molecular mechanism
• Targeted therapy
• Therapeutic tolerance

• Humans
• Breast Neoplasms/pathology
• Breast Neoplasms/drug therapy
• Breast Neoplasms/metabolism
• Breast Neoplasms/therapy
• Female
• Integrin beta1/metabolism
• Disease Progression
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/antagonists & inhibitors
• Prognosis
• Molecular Targeted Therapy/methods
• Gene Expression Regulation, Neoplastic
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology

• 82174016 the National Natural Science Foundation of China

• Extracellular matrix
• Integrin
• Secretome
• Stroma
• Tumor microenvironment
• Wound healing

• Humans
• Wound Healing
• Keratinocytes/metabolism
• Integrins/metabolism
• Integrins/genetics
• Skin Neoplasms/metabolism
• Skin Neoplasms/pathology
• Skin Neoplasms/genetics
• Epidermis/metabolism
• Animals
• Extracellular Matrix/metabolism
• Secretome/metabolism
• Carcinogenesis/metabolism
• Tumor Microenvironment
• Integrin alpha3beta1/metabolism
• Integrin alpha3beta1/genetics
• Skin/metabolism
• Skin/pathology

• R21 AR083049 NIAMS NIH HHS

• Cancer metastasis
• Drug target
• Integrinβ-1

• Cell Line, Tumor
• Integrin beta1/metabolism
• Signal Transduction
• Carrier Proteins
• Neoplasms/therapy

• 82103597 National Natural Science Foundation of China
• 81574189 National Natural Science Foundation of China
• 81001305 National Natural Science Foundation of China

• 3D tumor models
• Cancer
• Spheroids
• Tumor microenvironment

• Animals
• Neoplasms
• Cell Communication
• Disease Models, Animal
• Extracellular Matrix
• Tumor Microenvironment

• ERC-2018-STG-805411 European Research Council
• Fundação para a Ciência e a Tecnologia

• antagonists
• autoimmune disorders
• cancer
• inflammation
• integrin ligand-interactions
• integrins
• mechanism
• rational drug design
• structure

• Humans
• Integrins/metabolism
• Ligands
• Cell Adhesion Molecules
• Models, Molecular
• Neoplasms/drug therapy

• Akt
• Angiogenesis
• CD44
• Cancer stem cells
• Cancer-associated fibroblasts
• Endothelial cells
• Extracellular-signal-regulated kinase
• Integrins
• Mesenchymal stem cells
• Metastasis
• Osteopontin
• Pericytes
• Stromal cells
• Tumor microenvironment
• Tumor-associated macrophages
• Tumor-stroma interaction

Anti-PD-1/PD-L1 and anti-CTLA-4-based immune checkpoint blockade (ICB) immunotherapy have recently emerged as a breakthrough in human cancer treatment. Durable efficacy has been achieved in many types of human cancers. However, not all human cancers respond to current ICB immunotherapy and only a fraction of the responsive cancers exhibit efficacy. Osteopontin (OPN) expression is highly elevated in human cancers and functions as a tumor promoter. Emerging data suggest that OPN may also regulate immune cell function in the tumor microenvironment. This review aims at OPN function in human cancer progression and new findings of OPN as a new immune checkpoint. We propose that OPN compensates PD-L1 function to promote tumor immune evasion, which may underlie human cancer non-response to current ICB immunotherapy.

OPN is a multifunctional phosphoglycoprotein expressed in a wide range of cells, including osteoclasts, osteoblasts, neurons, epithelial cells, T, B, NK, NK T, myeloid, and innate lymphoid cells. OPN plays an important role in diverse biological processes and is implicated in multiple diseases such as cardiovascular, diabetes, kidney, proinflammatory, fibrosis, nephrolithiasis, wound healing, and cancer. In cancer patients, overexpressed OPN is often detected in the tumor microenvironment and elevated serum OPN level is correlated with poor prognosis. Initially identified in activated T cells and termed as early T cell activation gene, OPN links innate cells to adaptive cells in immune response to infection and cancer. Recent single cell RNA sequencing revealed that OPN is primarily expressed in tumor cells and tumor-infiltrating myeloid cells in human cancer patients. Emerging experimental data reveal a key role of OPN is tumor immune evasion through regulating macrophage polarization, recruitment, and inhibition of T cell activation in the tumor microenvironment. Therefore, in addition to its well-established direct tumor cell promotion function, OPN also acts as an immune checkpoint to negatively regulate T cell activation. The OPN protein level is highly elevated in peripheral blood of human cancer patients. OPN blockade immunotherapy with OPN neutralization monoclonal antibodies (mAbs) thus represents an attractive approach in human cancer immunotherapy.

• CD44
• MDSCs
• immune checkpoint
• immune evasion
• integrin
• osteopontin
• tumor-associated macrophage

• cancer metastasis
• drug resistance
• extracellular matrix
• integrins
• stemness
• therapeutic targeting

• T-cell lymphoma
• VEGF
• angiogenesis
• integrin αvβ3
• proliferation
• thyroid hormones

Osteopontin (OPN), a chemokine-like protein, plays a crucial role in the proliferation and metastasis of various cancers. However, how tumor stroma modulates the expression of neoplastic OPN and the multifaceted roles of OPN in head and neck cancer (HNC) are unclear. In this study, we tried to investigate the bridging role of OPN between tumor stroma and cancer cells.

Methods: Immunohistochemical staining and quantitative real-time PCR were used to detect OPN expression in HNC tissues, and the correlations between OPN expression and clinicopathologic features were then analyzed. We used a co-culture assay to study the modulatory role of IL-6 on OPN expression and immunoprecipitation analysis was used to determine the endogenous interaction between OPN and integrin αvβ3. Furthermore, a xenograft assay was carried out to confirm the tumor-promoting role and the potential therapeutic value of OPN in HNC.

Results: We found that OPN was significantly up-regulated in HNCs, and the elevated OPN was correlated with poor prognosis. Moreover, we identified IL-6 secreted by cancer-associated fibroblasts (CAFs) as the major upstream molecule that triggers the induction of neoplastic OPN. As such, during the interaction of fibroblasts and cancer cells, the increased neoplastic OPN induced by stromal IL-6 accelerated the growth, migration and invasion of cancer cells. More importantly, we also showed that soluble OPN could promote HNC progression via the integrin αvβ3-NF-kappa B pathway, and the combination of OPN and IL-6 had a better prognostic and diagnostic performance in HNC than either molecule alone.

Conclusion: Our study identified a novel modulatory role for OPN in HNC progression and further demonstrated that the combination of OPN and IL-6 might be a promising prognostic and diagnostic indicator as well as a potential cancer therapeutic target.

• Cancer-associated fibroblasts.
• Head and Neck Cancer
• IL-6
• NF-kappa B
• Osteopontin

Complex interactions between tumor and host cells regulate systemic tumor dissemination, a process that begins early at the primary tumor site and goes on until tumor cells detach themselves from the tumor mass and start migrating into the blood or lymphatic vessels. Metastatic cells colonize the target organs and are capable of surviving and growing at distant sites. In this context, osteopontin (OPN) appears to be a key determinant of the crosstalk between cancer cells and the host microenvironment, which in turn modulates immune evasion. OPN is overexpressed in several human carcinomas and has been implicated in inflammation, tumor progression, and metastasis. Thus, it represents one of the most attracting targets for cancer therapy. Within the tumor mass, OPN is secreted in various forms either by the tumor itself or by stroma cells, and it can exert either pro- or antitumorigenic effects according to the cell type and tumor microenvironment. Thus, targeting OPN for therapeutic purposes needs to take into account the heterogeneous functions of the multiple OPN forms with regard to cancer formation and progression. In this review, we will describe the role of systemic, tumor-derived, and stroma-derived OPN, highlighting its pivotal role at the crossroads of inflammation and tumor progression.

Tenascin-C (TNC) is highly expressed in cancer tissues. Its cellular sources are cancer and stromal cells, including fibroblasts/myofibroblasts, and also vascular cells. TNC expressed in cancer tissues dominantly contains large splice variants. Deposition of the stroma promotes the epithelial-mesenchymal transition, proliferation, and migration of cancer cells. It also facilitates the formation of cancer stroma including desmoplasia and angiogenesis. Integrin receptors that mediate the signals of TNC have also been discussed.

• CAF, cancer-associated fibroblasts
• ECM, extracellular matrix
• EDA, extra domain A
• EMT, epithelial-mesenchymal transition
• FAK, focal adhesion kinase
• FBG, fibrinogen-like globe
• FN, fibronectin
• FNIII, fibronectin type III-like
• HS, heparan sulfate
• ISH, in situ hybridization
• LAP, latency-associated peptide
• MMPs, matrix metalloproteinases
• OPN, osteopontin
• PDGF, platelet-derived growth factor
• RPTP, receptor protein-tyrosine phosphatase
• Stromal cell
• TGF, transforming growth factor
• TNC, tenascin-C
• VN, vitronectin
• cancer cell
• integrins
• splice variant
• tenascin-C

Adult T-cell leukemia (ATL) is a CD4⁺ T-cell neoplasm with a poor prognosis. A previous study has shown that there is a strong correlation between the secreted matricellular protein osteopontin (OPN) level and disease severity in ATL patients. Here, we investigated the role of OPN in ATL pathogenesis and the possible application of anti-OPN monoclonal antibody (mAb) for ATL immunotherapy in NOD/Shi-scid,IL-2Rg^null (NOG) mice.

Subcutaneous inoculation of ATL cell lines into NOG mice increased the plasma level of OPN, which significantly correlated with metastasis of the inoculated cells and survival time. Administration of an SVVYGLR motif-recognizing anti-OPN mAb resulted in inhibition not only of tumor growth but also of tumor invasion and metastasis. The number of fibroblast activating protein-positive fibroblasts was also reduced by this mAb. We then co-inoculated mouse embryonic fibroblasts (MEFs) isolated from wild-type (WT) or OPN knockout mice together with ATL-derived TL-OmI cells into the NOG mice. The mice co-inoculated with WT MEFs displayed a significant decrease in survival relative to those injected with TL-OmI cells alone and the absence of OPN in MEFs markedly improved the survival rate of TL-OmI-inoculated mice. In addition, tumor volume and metastasis were also reduced in the absence of OPN.

We showed that the xenograft NOG mice model can be a useful system for assessment of the physiological role of OPN in ATL pathogenesis. Using this xenograft model, we found that fibroblast-derived OPN was involved in tumor growth and metastasis, and that this tumor growth and metastasis was significantly suppressed by administration of the anti-OPN mAbs. Our findings will lead to a novel mAb-mediated immunotherapeutic strategy targeting against the interaction of OPN with integrins on the tumor of ATL patients.

The online version of this article (doi:10.1186/s12977-015-0225-x) contains supplementary material, which is available to authorized users.

• CAF, cancer-associated fibroblasts
• ECM, extracellular matrix
• EDA, extra domain A
• EMT, epithelial-mesenchymal transition
• FAK, focal adhesion kinase
• FBG, fibrinogen-like globe
• FN, fibronectin
• FNIII, fibronectin type III-like
• HS, heparan sulfate
• ISH, in situ hybridization
• LAP, latency-associated peptide
• MMPs, matrix metalloproteinases
• OPN, osteopontin
• PDGF, platelet-derived growth factor
• RPTP, receptor protein-tyrosine phosphatase
• Stromal cell
• TGF, transforming growth factor
• TNC, tenascin-C
• VN, vitronectin
• cancer cell
• integrins
• splice variant
• tenascin-C

• Breast cancer
• Chemoresistance
• Microenvironment
• Signaling molecule
• Targeted therapy