Transferrin receptor in primary and metastatic breast cancer: Evaluation of expression and experimental modulation to improve molecular targeting.

Background: Conjugation of transferrin (Tf) to imaging or nanotherapeutic agents is a promising strategy to target breast cancer. Since the efficacy of these biomaterials often depends on the overexpression of the targeted receptor, we set out to survey expression of transferrin receptor (TfR) in primary and metastatic breast cancer samples, including metastases and relapse, and investigate its modulation in experimental models.

Methods: Gene expression was investigated by datamining in twelve publicly-available datasets.

Targeted Therapy to β3 Integrin Reduces Chemoresistance in Breast Cancer Bone Metastases.

Breast cancer bone metastases are common and incurable. Tumoral integrin β3 (β3) expression is induced through interaction with the bone microenvironment. Although β3 is known to promote bone colonization, its functional role during therapy of established bone metastases is not known.

Nanotherapy delivery of c-myc inhibitor targets Protumor Macrophages and preserves Antitumor Macrophages in Breast Cancer.

Tumor-associated macrophages (TAMs) enhance tumor growth in mice and are correlated with a worse prognosis for breast cancer patients. While early therapies sought to deplete all macrophages, current therapeutics aim to reprogram pro-tumor macrophages (M2) and preserve those necessary for anti-tumor immune responses (M1). Recent studies have shown that c-MYC (MYC) is induced in M2 macrophages and where it regulates the expression of tumor-promoting genes.

HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemia.

Osteolytic bone lesions and hypercalcemia are common, serious complications in adult T cell leukemia/lymphoma (ATL), an aggressive T cell malignancy associated with human T cell leukemia virus type 1 (HTLV-1) infection. The HTLV-1 viral oncogene HBZ has been implicated in ATL tumorigenesis and bone loss. In this study, we evaluated the role of HBZ on ATL-associated bone destruction using HTLV-1 infection and disease progression mouse models.

HTLV-1 viral oncogene HBZ induces osteolytic bone disease in transgenic mice.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell malignancy that occurs in HTLV-1 infected patients. Most ATL patients develop osteolytic lesions and hypercalcemia of malignancy, causing severe skeletal related complications and reduced overall survival. The HTLV-1 virus encodes 2 viral oncogenes, Tax and HBZ.

Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases.

Bone metastases occur in approximately 70% of metastatic breast cancer patients, often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin β3 (β3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment.

Antagonizing Integrin β3 Increases Immunosuppression in Cancer.

Integrin β3 is critical for tumor invasion, neoangiogenesis, and inflammation, making it a promising cancer target. However, preclinical and clinical data of integrin β3 antagonists have demonstrated no benefit or worse outcomes. We hypothesized that integrin β3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin β3 in macrophage lineage cells (β3KOM).

Dual-therapy with αvβ3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model.

Fumagillin, an unstable anti-angiogenesis mycotoxin, was synthesized into a stable lipase-labile prodrug and incorporated into integrin-targeted lipid-encapsulated nanoparticles (αvβ3-Fum-PD NP). Dual anti-angiogenic therapy combining αvβ3-Fum-PD NP with zoledronic acid (ZA), a long-acting osteoclast inhibitor with proposed anti-angiogenic effects, was evaluated. In vitro, αvβ3-Fum-PD NP reduced (P<0.

CXCR4 Protein Epitope Mimetic Antagonist POL5551 Disrupts Metastasis and Enhances Chemotherapy Effect in Triple-Negative Breast Cancer.

The SDF-1 receptor CXCR4 has been associated with early metastasis and poorer prognosis in breast cancers, especially the most aggressive triple-negative subtype. In line with previous reports, we found that tumoral CXCR4 expression in patients with locally advanced breast cancer was associated with increased metastases and rapid tumor progression. Moreover, high CXCR4 expression identified a group of bone marrow-disseminated tumor cells (DTC)-negative patients at high risk for metastasis and death.

Loss of LARGE2 disrupts functional glycosylation of α-dystroglycan in prostate cancer.

Dystroglycan (DG) is a cell surface receptor for extracellular matrix proteins and is involved in cell polarity, matrix organization, and mechanical stability of tissues. Previous studies documented loss of DG protein expression and glycosylation in a variety of cancer types, but the underlying mechanisms and the functional consequences with respect to cancer progression remain unclear. Here, we show that the level of expression of the βDG subunit as well as the glycosylation status of the αDG subunit inversely correlate with the Gleason scores of prostate cancers; furthermore, we show that the functional glycosylation of αDG is substantially reduced in prostate cancer metastases.

Dystroglycan is not required for maintenance of the luminal epithelial basement membrane or cell polarity in the mouse prostate.

Background: Dystroglycan is a cell-surface receptor for extracellular matrix proteins including laminins and perlecan. Prior studies have shown its involvement in assembly and/or maintenance of basement membrane structures, cell polarity and tissue morphogenesis; and its expression is often reduced in prostate and other cancers. However, the role of dystroglycan in normal epithelial tissues such as the prostate is unclear.

Endothelin-1 inhibits prostate cancer growth in vivo through vasoconstriction of tumor-feeding arterioles.

The vasoactive peptide endothelin-1 (ET-1) has been implicated in promoting the progression of prostate and other cancers though its precise mechanism(s)-of-action remain unclear. To better define the role of ET-1 in prostate cancer progression, we generated prostate cancer cell lines (PC-3 and 22Rv1) that express elevated levels of ET-1. As anticipated, increased ET-1 lead to modest autocrine growth stimulation of PC-3 cells in monolayer culture and increased colony formation in soft agar by both cell lines.