CCL21-CCR7 signaling promotes microglia/macrophage recruitment and chemotherapy resistance in glioblastoma.

Glioblastoma (GBM) is the most common and fatal primary tumor of the central nervous system (CNS) and current treatments have limited success. Chemokine signaling regulates both malignant cells and stromal cells of the tumor microenvironment (TME), constituting a potential therapeutic target against brain cancers. Here, we investigated the C-C chemokine receptor type 7 (CCR7) and the chemokine (C-C-motif) ligand 21 (CCL21) for their expression and function in human GBM and then assessed their therapeutic potential in preclinical mouse GBM models. In GBM patients, CCR7 expression positively associated with a poor survival. CCL21-CCR7 signaling was shown to regulate tumor cell migration and proliferation while also controlling tumor associated microglia/macrophage recruitment and VEGF-A production, thereby controlling vascular dysmorphia. Inhibition of CCL21-CCR7 signaling led to an increased sensitivity to temozolomide-induced tumor cell death. Collectively, our data indicate that drug targeting of CCL21-CCR7 signaling in tumor and TME cells is a therapeutic option against GBM.

The multiple functions of PrPC in physiological, cancer, and neurodegenerative contexts.

Cellular prion protein (PrPC) is a highly conserved glycoprotein, present both anchored in the cell membrane and soluble in the extracellular medium. It has a diversity of ligands and is variably expressed in numerous tissues and cell subtypes, most notably in the central nervous system (CNS). Its importance has been brought to light over the years both under physiological conditions, such as embryogenesis and immune system homeostasis, and in pathologies, such as cancer and neurodegenerative diseases. During development, PrPC plays an important role in CNS, participating in axonal growth and guidance and differentiation of glial cells, but also in other organs such as the heart, lung, and digestive system. In diseases, PrPC has been related to several types of tumors, modulating cancer stem cells, enhancing malignant properties, and inducing drug resistance. Also, in non-neoplastic diseases, such as Alzheimer's and Parkinson's diseases, PrPC seems to alter the dynamics of neurotoxic aggregate formation and, consequently, the progression of the disease. In this review, we explore in detail the multiple functions of this protein, which proved to be relevant for understanding the dynamics of organism homeostasis, as well as a promising target in the treatment of both neoplastic and degenerative diseases.

The multiple functions of the co-chaperone stress inducible protein 1.

Stress inducible protein 1 (STI1) is a co-chaperone acting with Hsp70 and Hsp90 for the correct client proteins' folding and therefore for the maintenance of cellular homeostasis. Besides being expressed in the cytosol, STI1 can also be found both in the cell membrane and the extracellular medium playing several relevant roles in the central nervous system (CNS) and tumor microenvironment. During CNS development, in association with cellular prion protein (PrPc), STI1 regulates crucial events such as neuroprotection, neuritogenesis, astrocyte differentiation and survival. In cancer, STI1 is involved with tumor growth and invasion, is undoubtedly a pro-tumor factor, being considered as a biomarker and possibly therapeutic target for several malignancies. In this review, we discuss current knowledge and new findings on STI1 function as well as its role in tissue homeostasis, CNS and tumor progression.

An Uncommon Lung Neoplasm in a Young Patient: Diagnostic Challenges.

BACKGROUND Adenosquamous carcinoma of the lung (ASC) is a rare subtype of non-small-cell lung carcinoma (NSCLC), histologically defined by the presence of both squamous cell carcinoma and adenocarcinoma components. This aggressive malignancy has been rarely described in young female patients. Due to its low incidence and difficult-to-establish preoperative diagnosis, little is known about the complete clinical course for young patients with this specific NSCLC subtype. Moreover, a history of smoking is positively associated with ASC, but evidence for an association with exposure to secondhand smoke is sparse. CASE REPORT We present the case of a previously healthy 29-year-old woman with a long-standing history of secondhand smoke exposure, who was ultimately diagnosed with advanced ASC via fiberoptic bronchoscopy with transbronchial biopsy after a number of different investigations and treatments performed outside our service. She had visited many clinicians in 4 months of symptoms, initially presented as thoracic pain and cough thought to be due to a complicated pneumonia. Symptoms progressed despite empiric treatment and eventually included low back pain, weight loss, and night sweats. The hypothesis of tuberculosis was then investigated and discarded, at which point, 3 months after the onset of symptoms, she had a CT scan of the chest, revealing a pulmonary mass. She was referred to our hospital to further investigate this finding via fiberoptic bronchoscopy with transbronchial biopsy. During the procedure, she experienced an acute exacerbation of the low back pain, which prompted her admission in the Emergency Department, and she was later admitted to our pneumology ward. An extensive treatment plan including chemotherapy and radiotherapy was initially started, but could not be completed due to rapid disease progression, defined by pulmonary and spine metastatic implants, which limited treatment to palliative care. The patient died 6 months after the initial onset of symptoms. CONCLUSIONS This case report shows the clinical course of a difficult and rare diagnosis, and demonstrates the high level of suspicion required for the early diagnosis of lung neoplasms in young patients.