Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer.

Breast cancer, the most frequent female malignancy, is often curable when detected at an early stage. The treatment of metastatic breast cancer is more challenging and may be unresponsive to conventional therapy. Immunotherapy is crucial for treating metastatic breast cancer, but its resistance is a major limitation. The tumor microenvironment (TME) is vital in modulating the immunotherapy response. Various tumor microenvironmental components, such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), are involved in TME modulation to cause immunotherapy resistance. This review highlights the role of stromal cells in modulating the breast tumor microenvironment, including the involvement of CAF-TAM interaction, alteration of tumor metabolism leading to immunotherapy failure, and other latest strategies, including high throughput genomic screening, single-cell and spatial omics techniques for identifying tumor immune genes regulating immunotherapy response. This review emphasizes the therapeutic approach to overcome breast cancer immune resistance through CAF reprogramming, modulation of TAM polarization, tumor metabolism, and genomic alterations.

Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis.

Translocation renal cell carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed clear cell RCC driver) disrupted nephrogenesis and glomerular development, causing neonatal death, while the clear cell RCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as alveolar soft part sarcoma) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an epithelial-mesenchymal transition. Electron microscopy of tRCC tumors showed lysosome expansion, and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses encompassing an institutional human tRCC cohort (including a hitherto unreported SFPQ-TFEB fusion) and a variety of tumorgraft models (ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3, RBM10-TFE3, and MALAT1-TFEB) disclosed significant convergence in canonical pathways (cell cycle, lysosome, and mTORC1) and less established pathways such as Myc, E2F, and inflammation (IL-6/JAK/STAT3, interferon-γ, TLR signaling, systemic lupus, etc.). Therapeutic trials (adjusted for human drug exposures) showed antitumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis, including the cell of origin, and characterizes diverse mouse models available for research.

Heterotypic signaling of cancer-associated fibroblasts in shaping the cancer cell drug resistance.

The context-dependent reciprocal interaction between the cancer cells and surrounding fibroblasts is imperative for regulating malignant potential, metabolic reprogramming, immunosuppression, and ECM deposition. However, recent evidence also suggests that cancer-associated fibroblasts induce chemoresistance in cancer cells to various anticancer regimens. Because of the protumorigenic function of cancer-associated fibroblasts, these stromal cell types have emerged as fascinating therapeutic targets for cancer. However, this notion was recently challenged by studies that targeted cancer-associated fibroblasts and highlighted the underlying heterogeneity by identifying a subset of these cells with tumor-restricting functions. Hence, it is imperative to understand the heterogeneity and heterotypic signaling of cancer-associated fibroblasts to target tumor-promoting signaling processes by sparing tumor-restricting ones. In this review, we discuss the heterogeneity and heterotypic signaling of cancer-associated fibroblasts in shaping drug resistance and also list the cancer-associated fibroblast-targeting therapeutics.

Development and characterization of a patient­derived orthotopic xenograft of therapy­resistant breast cancer.

Numerous years of cell line­based studies have enhanced the current understanding of cancer and its treatment. However, limited success has been achieved in treating hormone receptor­positive, HER2­negative metastatic breast cancers that are refractory to treatment. The majority of cancer cell lines are unsuitable for use as pre­clinical models that mimic this critical and often fatal clinical type, since they are derived from treatment­naive or non­metastatic breast cancer cases. The aim of the present study was to develop and characterize patient­derived orthotopic xenografts (PDOXs) from patients with endocrine hormone receptor­positive, HER2­negative metastatic breast cancer who had relapsed on therapy. A patient who progressed on endocrine hormone therapy provided her tumor via a biobank. This tumor was implanted in mice. It was then serially passaged by implanting PDOX tumor fragments into another set of mice to develop further generations of PDOXs. These tissues were characterized using various histological and biochemical techniques. Histological, immunofluorescence and western blot analyses indicated that the PDOX tumors retained a similar morphology, histology and subtype­specific molecular features to that of the patient's tumor. The present study successfully established PDOXs of hormone­resistant breast cancer and characterized them in comparison with those derived from the original breast cancer tissue of the patient. The data highlight the reliability and usefulness of PDOX models for studies of biomarker discovery and preclinical drug screening. The present study was registered with the clinical trial registry of India (CTRI; registration no. CTRI/2017/11/010553; registered on 17/11/2017).

Antiproliferative and apoptotic potential of methotrexate lipid nanoparticles in a murine breast cancer model.

Aim: To evaluate the efficacy of novel methotrexate-loaded nanoparticles (MTX-NPs) in vitro and in vivo in the treatment of breast cancer. Materials & methods: MTX-NPs were tested for cellular uptake, cell viability, cell cycle, cellular wound migration and changes in tumor volume using characterized NPs. Results: The solid lipid NPs (SLNPs) showed strong cellular uptake, increased apoptosis, controlled cytotoxicity at lower IC50 of methotrexate and a sizable reduction in tumor burden. Conclusion: MTX-NP oral formulation can be a promising candidate in breast cancer treatment with improved cellular uptake and in vivo efficacy.

Herbal medicine AnoSpray suppresses proinflammatory cytokines COX-2 and RANTES in the management of hemorrhoids, acute anal fissures and perineal wounds.

Hemorrhoids, anal fistula and fissure are common anorectal complications. Anorectal diseases are associated with severe pain, inflammation, swelling, itching and bleeding. These diseases may be managed with different medical treatments or surgical procedures, depending on their severity. Surgical procedures, however, are highly invasive and are associated with higher costs and the possibility of recurrence. In addition, surgical removal of fistula-in-ano leads to the formation of perineal wounds. Therefore, developing therapeutic interventions that are effective in alleviating inflammation and pain are desirable for the effective management of anorectal diseases. Herbal compounds have previously been indicated to suppress inflammation and pain in different pathological conditions. The aim of the present study was to examine the effects elicited by a polyherbal formulation, AnoSpray®, on the migration of inflammatory cells and on the expression of inflammatory cytokines in anorectal diseases. The effect of AnoSpray on cell viability and migration was studied using MTT and wound-migration assays, respectively. Furthermore, the effects of AnoSpray on the expression of the inflammatory cytokines regulated upon activation, normal T cell expressed and presumably secreted (RANTES) and VEGF, as well as on cyclooxygenase-2 (COX)-2, were investigated using western blot analysis. The expression of RANTES and COX-2 in human hemorrhoid specimens was also analyzed to corroborate the in vitro findings. The results obtained revealed that AnoSpray did not exhibit any cytotoxic effects; however, it did lead to a significant suppression in the migration of RAW 264.7 and BJ cells. Furthermore, the results suggested that AnoSpray suppressed the expression of the inflammatory cytokines RANTES and VEGF, and also the expression of COX-2. In addition, RANTES and COX-2 were significantly downregulated in the clinical specimens of AnoSpray-treated hemorrhoids compared with the controls. Taken together, the results of the present study suggested that AnoSpray may be a potential therapeutic agent in the treatment of bleeding hemorrhoids, anal fissures and perineal wounds.

Osteopontin Signaling in Shaping Tumor Microenvironment Conducive to Malignant Progression.

Context-dependent reciprocal crosstalk between cancer and surrounding stromal cells in the tumor microenvironment is imperative for the regulation of various hallmarks of cancer. A myriad of growth factors, chemokines, and their receptors aids in the interaction between cancer cells and tumor microenvironmental components. Osteopontin is a chemokine-like protein, overexpressed in different types of cancers. Osteopontin plays a crucial role in orchestrating dialogue between cancer and stromal cells. Osteopontin, in tumor microenvironment, is produced in tumor as well as stromal cells. Tumor-derived osteopontin regulates proliferation, migration, activation, and differentiation of different types of stromal cells. Osteopontin secreted from tumor cells regulates the generation of cancer-associated fibroblasts from resident fibroblasts and mesenchymal stem cells. Osteopontin also shapes immunosuppressive tumor microenvironment by controlling regulatory T cells and tumor-associated macrophages. Moreover, secretion of osteopontin from tumor stroma has been highly documented. Stromal cell-derived osteopontin induces epithelial-to-mesenchymal transition, angiogenesis, metastasis, and cancer stem cell enrichment. Tumor- or stroma-derived osteopontin mainly functions through binding with cell surface receptors, integrins and CD44, and activates downstream signaling events like PI-3 kinase/Akt and MAPK pathways. Presumably, disrupting the communication between the tumor cells and surrounding microenvironment by targeting osteopontin-regulated signaling using specific antibodies, small-molecule inhibitors, and chemotherapeutic agents is a novel therapeutic strategy for clinical management of cancer.

MiRNA-146a/AKT/ß-Catenin Activation Regulates Cancer Stem Cell Phenotype in Oral Squamous Cell Carcinoma by Targeting CD24.

CD44highCD24low population has been previously reported as cancer stem cells (CSCs) in Oral Squamous Cell Carcinoma (OSCC). Increasing evidence suggests potential involvement of microRNA (miRNA) network in modulation of CSC properties. MiRNAs have thus emerged as crucial players in tumor development and maintenance. However, their role in maintenance of OSCC stem cells remains unclear. Here we report an elevated expression of miR-146a in the CD44highCD24low population within OSCC cells and primary HNSCC tumors. Moreover, over-expression of miR-146a results in enhanced stemness phenotype by augmenting the CD44highCD24low population. We demonstrate that miR-146a stabilizes ß-catenin with concomitant loss of E-cadherin and CD24. Interestingly, CD24 is identified as a novel functional target of miR-146a and ectopic expression of CD24 abrogates miR-146a driven potential CSC phenotype. Mechanistic analysis reveals that higher CD24 levels inhibit AKT phosphorylation leading to ß-catenin degradation. Using stably expressing miR-146a/CD24 OSCC cell lines, we also validate that the miR-146a/CD24/AKT loop significantly alters tumorigenic ability in vivo. Furthermore, we confirmed that ß-catenin trans-activates miR-146a, thereby forming a positive feedback loop contributing to stem cell maintenance. Collectively, our study demonstrates that miR-146a regulates CSCs in OSCC through CD24-AKT-ß-catenin axis.

Polyherbal formulation Anoac­H suppresses the expression of RANTES and VEGF for the management of bleeding hemorrhoids and fistula.

Hemorrhoids and fistula are considered the most common anorectal conditions in the general population. These conditions affect the quality of a patient's life by causing pain and bleeding during defecation or even in the resting state. Lower grades of hemorrhoids may be controlled by traditional measures. However, surgery is an effective treatment option in recurrent­lower and higher­grade hemorrhoids. Surgical procedures are associated with various complications, including pain and delayed wound healing. Recurrence of hemorrhoids is also a major concern in the post­operative period. An anal fistula is the connection between the anus and the skin and causes severe pain, swelling, as well as blood and pus discharge. Fistula has serious social and economic consequences. Hence, it is important to understand the pathophysiology and molecular pathology of hemorrhoids and fistula, to identify the molecular targets and to develop pharmacological­interventions. In a previous study by our group, the polyherbal formulation Anoac­H was developed for the treatment of different stages of hemorrhoids and fistula, and it was demonstrated that Anoac­H is an effective formulation for treating hemorrhoids. However, the molecular mode of action of Anoac­H on hemorrhoids and fistula had remained elusive. In the present study, it was determined that this formulation reduces the migration of mesenchymal (fibroblasts) and immune (RAW 264.7) cells without affecting their viability. It was also observed that Anoac­H suppresses the expression of regulated upon activation, normal T cell expressed and presumably secreted (RANTES) and VEGF in fibroblasts and macrophages. Inflammation and elevated expression of RANTES and VEGF were observed in hemorrhoids and fistula. However, inflammation, as well as the expression of RANTES and VEGF, were significantly reduced in treated human hemorrhoid and fistula tissues as compared to untreated ones, confirming the in vitro results.

Tumor-derived osteopontin drives the resident fibroblast to myofibroblast differentiation through Twist1 to promote breast cancer progression.

Tumor-stroma interactions are important determinants for the disease course in cancer. While stromal influence has been known to often play a tumor-promoting role, incomplete mechanistic insight into this phenomenon has prevented its therapeutic targeting. Stromal fibroblasts can be activated by tumor cells to differentiate into cancer-associated fibroblasts (CAFs), that exhibit the traits of myofibroblasts, and in turn, they increase cancer aggressiveness. Here, we report the crosstalk between the cancer cells and stromal fibroblasts that leads to tumor progression. The process is initiated by secretion of a chemokine like protein, osteopontin (OPN) from the cancer cells that differentiates the fibroblasts to myofibroblasts. Tumor-derived OPN achieves this transition by engaging CD44 and αvß3 integrins on the fibroblast surface, which mediates signaling via Akt and ERK to induce Twist1-dependent gene expression. The OPN-driven CAFs then secrete CXCL12, which in turn triggers epithelial to mesenchymal transition (EMT) in the tumor cells. OPN, produced by the cancer cells, and CXCL12, secreted by activated fibroblasts, are necessary and sufficient to perpetuate the crosstalk. Knocking out OPN in carcinogen-induced mammary tumors or knocking down OPN in cancer cells and fibroblast co-implanted xenografts abrogates myofibroblast differentiation, Twist1, and CXCL12 expression. OPN expression is correlated with CAF-specific gene signature as shown by breast tumor tissue microarray consisting of 100 patient specimens. Bioinformatics analyses have confirmed that the expression of OPN is significantly correlated with the expression of myofibroblast-specific markers as demonstrated in human breast carcinoma dataset of 2509 patients. Our findings describe OPN and CXCL12 act as compelling targets to curb the tumor-promoting features of the stromal components and further suggested that OPN-regulated CXCL12 network might act as potential therapeutic target for the management of CAF-mediated breast cancer progression.

Desialylation of Sonic-Hedgehog by Neu2 Inhibits Its Association with Patched1 Reducing Stemness-Like Properties in Pancreatic Cancer Sphere-forming Cells.

Cancer stem cells (CSCs) are crucial regulators of tumor recurrence/progression. The maintenance of CSCs is dependent on aberrant activation of various pathways, including Hedgehog. Prevalent sialylations contribute to aggressiveness in CSCs. Here, we have addressed the role of sialylation in regulating stemness-like properties of pancreatic cancer sphere-forming cells (PCS) through modulation of the Hedgehog (Hh) pathway. The status of CD133/CD44/surface-sialylation was checked by flow cytometry and effects of Neu2 overexpression in PCS were compared using qPCR, immunoblotting, co-immunoprecipitation and also by colony-formation assays. The work was also validated in a xenograft model after Neu2 overexpression. Neu2 and Shh status in patient tissues were examined by immunohistochemistry. PCS showed higher Hh-pathway activity and sialylation with reduced cytosolic-sialidase (Neu2). Neu2 overexpression caused desialylation of Shh, thereby reducing Shh-Patched1 binding thus causing decreased Hh-pathway activity with lower expression of Snail/Slug/CyclinD1 leading to reduction of stemness-like properties. Neu2-overexpression also induced apoptosis in PCS. Additionally, Neu2-overexpressed PCS demonstrated lower mTORC2 formation and inhibitory-phosphorylation of Gsk3ß, reflecting a close relationship with reduced Hh pathway. Moreover, both Neu2 and Rictor (a major component of mTORC2) co-transfection reduced stem cell markers and Hh-pathway activity in PCS. Neu2-overexpressed tumors showed reduction in tumor mass with downregulation of stem cell markers/Shh/mTOR and upregulation of Bax/Caspase8/Caspase3. Thus, we established that reduced sialylation by Neu2 overexpression leads to decreased stemness-like properties by desialylation of Shh, which impaired its association with Patched1 thereby inhibiting the Hh pathway. All these may be responsible for enhanced apoptosis in Neu2-overexpressed PCS.

Breast cancer stem cells: Biology and therapeutic implications.

Breast cancer remains to be a dreadful disease even with several advancements in radiation and chemotherapies, owing to the drug resistance and tumor relapse caused by breast cancer stem cells. Cancer stem cells are a minute population of cells of solid tumors which show self-renewal and differentiation properties as well as tumorigenic potential. Several signaling pathways including Notch, Hippo, Wnt and Hedgehog and tumor-stroma exchanges play a critical role in the self-renewal and differentiation of cancer stem cells in breast cancer. Cancer stem cells can grow anchorage-independent manner so they disseminate to different parts of the body to form secondary tumors. Cancer stem cells promote angiogenesis by dedifferentiating to endothelial cells as well as secreting proangiogenic and angiogenic factors. Moreover, multidrug resistance genes and drug efflux transporters expressed in breast cancer stem cells confer resistance to various conventional chemotherapeutic drugs. Indeed, these therapies are recognised to enhance the percent of cancer stem cell population in tumors leading to cancer relapse with increased aggressiveness. Hence, devising the therapeutic interventions to target cancer stem cells would be useful in increasing patients' survival rates. In addition, targeting the self-renewal pathways and tumor-stromal cross-talk helps in eradicating this population. Reversal of the cancer stem cell-mediated drug resistance would increase the sensitivity to various conventional drugs for the effective management of breast cancer. In this review, we have discussed the cancer stem cell origin and their involvement in angiogenesis, metastasis and therapy-resistance. We have also summarized different therapeutic approaches to eradicate the same for the successful treatment of breast cancer.

Impact of semaphorin expression on prognostic characteristics in breast cancer.

Breast cancer is one of the major causes of cancer-related deaths among women worldwide. Aberrant regulation of various growth factors, cytokines, and other proteins and their receptors in cancer cells drives the activation of various oncogenic signaling pathways that lead to cancer progression. Semaphorins are a class of proteins which are differentially expressed in various types of cancer including breast cancer. Earlier, these proteins were known to have a major function in the nerve cell adhesion, migration, and development of the central nervous system. However, their role in the regulation of several aspects of tumor progression has eventually emerged. There are over 30 genes encoding the semaphorins, which are divided into eight subclasses. It has been reported that some members of semaphorin classes are antiangiogenic and antimetastatic in nature, whereas others act as proangiogenic and prometastatic genes. Because of their differential expression and role in angiogenesis and metastasis, semaphorins emerged as one of the important prognostic factors for appraising breast cancer progression.

The Biology and Therapeutic Implications of Tumor Dormancy and Reactivation.

Advancements in the early detection of cancer coupled with improved surgery, radiotherapy, and adjuvant therapy led to substantial increase in patient survival. Nevertheless, cancer metastasis is the leading cause of death in several cancer patients. The majority of these deaths are associated with metastatic relapse kinetics after a variable period of clinical remission. Most of the cancer recurrences are thought to be associated with the reactivation of dormant disseminated tumor cells (DTCs). In this review, we have summarized the cellular and molecular mechanisms related to DTCs and the role of microenvironmental niche. These mechanisms regulate the dormant state and help in the reactivation, which leads to metastatic outgrowth. Identification of novel therapeutic targets to eliminate these dormant tumor cells will be highly useful in controlling the metastatic relapse-related death with several cancers.

Receptor tyrosine kinases (RTKs) in breast cancer: signaling, therapeutic implications and challenges.

Breast cancer is a multifactorial disease and driven by aberrant regulation of cell signaling pathways due to the acquisition of genetic and epigenetic changes. An array of growth factors and their receptors is involved in cancer development and metastasis. Receptor Tyrosine Kinases (RTKs) constitute a class of receptors that play important role in cancer progression. RTKs are cell surface receptors with specialized structural and biological features which respond to environmental cues by initiating appropriate signaling cascades in tumor cells. RTKs are known to regulate various downstream signaling pathways such as MAPK, PI3K/Akt and JAK/STAT. These pathways have a pivotal role in the regulation of cancer stemness, angiogenesis and metastasis. These pathways are also imperative for a reciprocal interaction of tumor and stromal cells. Multi-faceted role of RTKs renders them amenable to therapy in breast cancer. However, structural mutations, gene amplification and alternate pathway activation pose challenges to anti-RTK therapy.

p53 gain-of-function mutations increase Cdc7-dependent replication initiation.

Cancer-associated p53 missense mutants confer gain of function (GOF) and promote tumorigenesis by regulating crucial signaling pathways. However, the role of GOF mutant p53 in regulating DNA replication, a commonly altered pathway in cancer, is less explored. Here, we show that enhanced Cdc7-dependent replication initiation enables mutant p53 to confer oncogenic phenotypes. We demonstrate that mutant p53 cooperates with the oncogenic transcription factor Myb in vivo and transactivates Cdc7 in cancer cells. Moreover, mutant p53 cells exhibit enhanced levels of Dbf4, promoting the activity of Cdc7/Dbf4 complex. Chromatin enrichment of replication initiation factors and subsequent increase in origin firing confirm increased Cdc7-dependent replication initiation in mutant p53 cells. Further, knockdown of CDC7 significantly abrogates mutant p53-driven cancer phenotypes in vitro and in vivo Importantly, high CDC7 expression significantly correlates with p53 mutational status and predicts poor clinical outcome in lung adenocarcinoma patients. Collectively, this study highlights a novel functional interaction between mutant p53 and the DNA replication pathway in cancer cells. We propose that increased Cdc7-dependent replication initiation is a hallmark of p53 gain-of-function mutations.

MiRNA199a-3p suppresses tumor growth, migration, invasion and angiogenesis in hepatocellular carcinoma by targeting VEGFA, VEGFR1, VEGFR2, HGF and MMP2.

Increasing significance of tumor-stromal interaction in development and progression of cancer implies that signaling molecules in the tumor microenvironment (TME) might be the effective therapeutic targets for hepatocellular carcinoma (HCC). Here, the role of microRNA miR-199a-3p in the regulation of TME and development of HCC has been investigated by several in vitro and in vivo assays. Expression of miR-199a-3p was observed significantly low in HCC tissues and its overexpression remarkably inhibited in vivo tumor growth and metastasis to lung in NOD-SCID mice. In vitro restoration of miR-199a-3p expression either in endothelial cells (ECs) or in cancer cells (CACs) significantly diminished migration of ECs in co-culture assay. Again incubation of miR-199a-3p transfected ECs with either conditioned media (CM) of CACs or recombinant VEGF has reduced tube formation, in ECs and it was also dropped upon growth in CM of either anti-VEGF antibody-treated or miR-199a-3p-transfected CACs. In addition, bioinformatics and luciferase-reporter assays revealed that miR-199a-3p inhibited VEGF secretion from CACs and VEGFR1 and VEGFR2 expression on ECs and thus restricted cross talk between CACs and ECs. Again, restoration of miR-199a-3p in hepatic stellate cells (HSCs) reduced migration and invasion of CACs in co-culture assay, while it was enhanced by the overexpression of HGF suggesting miR-199a-3p has hindered HSC-CACs cross talk probably by inhibiting HGF and regulating matrix metalloproteinase MMP2, which were found as targets of miR-199a-3p subsequently by luciferase-reporter assay and gelatin zymography, respectively. Thus, these findings collectively highlight that miR-199a-3p restricts metastasis, invasion and angiogenesis in HCC and hence it may be considered as one of the powerful effective therapeutics for management of HCC patients.

Osteopontin as a therapeutic target for cancer.

INTRODUCTION: Cancer is a complex pathological disorder, established as a result of accumulation of genetic and epigenetic changes, which lead to adverse alterations in the cellular phenotype. Tumor progression involves intricate signaling mediated through crosstalk between various growth factors, cytokines and chemokines. Osteopontin (OPN), a chemokine-like protein, is involved in promotion of neoplastic cancer into higher grade malignancies by regulating various facets of tumor progression such as cell proliferation, angiogenesis and metastasis. AREAS COVERED: Tumors as well as stroma-derived OPN play key roles in various signaling pathways involved in tumor growth, angiogenesis and metastasis. OPN derived from tumor-activated macrophages modulates the tumor microenvironment and thereby regulate melanoma growth and angiogenesis. OPN also regulates hypoxia-inducible factor-1α-dependent VEGF expression leading to breast tumor growth and angiogenesis in response to hypoxia. Thus, a clear understanding of the molecular mechanism underlying OPN-mediated regulation will shed light on exciting avenues for further investigation of targeted therapies. Silencing of OPN using RNAi technology, blocking OPN activity using specific antibodies and small-molecule inhibitors might provide novel strategies, which would aid in developing effective therapeutics for the treatment of various types of cancer. EXPERT OPINION: This review focuses on new possibilities to exploit OPN as a tumor and stroma-derived therapeutic target to combat cancer.