chondroitin-sulfates and Esophageal-Neoplasms

Extracellular matrix, either produced by cancer cells or by cancer-associated fibroblasts, influences angiogenesis, invasion, and metastasis. Chondroitin/dermatan sulfate (CS/DS) proteoglycans, which occur both in the matrix and at the cell surface, play important roles in these processes. The unique feature that distinguishes DS from CS is the presence of iduronic acid (IdoA) in DS. Here, we report that CS/DS is increased five-fold in human biopsies of esophagus squamous cell carcinoma (ESCC), an aggressive tumor with poor prognosis, as compared with normal tissue. The main IdoA-producing enzyme, DS epimerase 1 (DS-epi1), together with the 6-O- and 4-O-sulfotransferases, were highly upregulated in ESCC biopsies. Importantly, CS/DS structure in patient tumors was significantly altered compared with normal tissue, as determined by sensitive mass spectrometry. To further understand the roles of IdoA in tumor development, DS-epi1 expression, and consequently IdoA content, was downregulated in ESCC cells. IdoA-deficient cells exhibited decreased migration and invasion capabilities in vitro, which was associated with reduced cellular binding of hepatocyte growth factor, inhibition of pERK-1/2 signaling, and deregulated actin cytoskeleton dynamics and focal adhesion formation. Our findings show that IdoA in DS influences tumorigenesis by affecting cancer cell behavior. Therefore, downregulation of IdoA by DS-epi1 inhibitors may represent a new anticancer therapy.

Topics: Adult; Aged; Aged, 80 and over; Antigens, Neoplasm; Carcinoma, Squamous Cell; Cell Movement; Chondroitin Sulfates; Dermatan Sulfate; DNA-Binding Proteins; Esophageal Neoplasms; Female; Flow Cytometry; Gene Knockdown Techniques; Humans; Iduronic Acid; Immunohistochemistry; Male; Mass Spectrometry; Middle Aged; Neoplasm Proteins

In 23 cases of carcinoma of the head and neck, the combined use of Somatostatin and/or its analogue Octreotide, prolactin inhibitors, Melatonin, Retinoids, Vitamin E, Vitamin D3, Vitamin C, Calcium, chondroitin-sulphate, and minimal oral doses of cyclophosphamide (50-100 mg/day) led to a decided increase in survival with respect to the median values reported in the literature for the same tumours and stages, together with an evident improvement in the quality of life, partial or complete objective responses and, in some cases, complete and stable cure with functional recovery. The rationale and the mechanisms of molecular biology of the treatment are discussed, showing that the treatment has a differentiating, apoptotic, antiproliferative, antiangiogenic and antimetastatic effect, and, unlike chemo- and/or radiotherapy, preserves and enhances the trophism and functionality of organs, tissues and immunitary and antitumoral homeostasis. This result, achieved without toxicity, demonstrates the efficacy of this biological multitherapy (Prof. Luigi Di Bella's method or DBM) and is in agreement with the positive results already published on the use of the DBM in various neoplastic diseases. We believe it is of use to report these cases to invite greater interest in the possibilities opened up by this biological multitherapy.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antioxidants; Calcium; Carcinoma, Medullary; Carcinoma, Squamous Cell; Chondroitin Sulfates; Cyclophosphamide; Drug Therapy, Combination; Esophageal Neoplasms; Head and Neck Neoplasms; Humans; Melatonin; Octreotide; Retinoids; Retrospective Studies; Sarcoma; Vitamins