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Cancer cell cannibalism is currently defined as a phenomenon in which an ensemble of a larger cell containing a smaller one, often in a big cytoplasmic vacuole, is detected in either cultured tumor cells or a tumor sample. After almost one century of considering this phenomenon as a sort of neglected curiosity, some recent studies have first proposed tumor cell cannibalism as a sort of "aberrant phagocytosis", making malignant cells very similar to professional phagocytes. Later, further research has shown that, differently to macrophages, exclusively ingesting exogenous material, apoptotic bodies, or cell debris, tumor cells are able to engulf other cells, including lymphocytes and erythrocytes, either dead or alive, with the main purpose to feed on them. This phenomenon has been associated to the malignancy of tumors, mostly exclusive of metastatic cells, and often associated to poor prognosis. The cannibalistic behavior increased depending on the microenvironmental condition of tumor cells, such as low nutrient supply or low pH, suggesting its key survival option for malignant cancers. However, the evidence that malignant cells may cannibalize tumor-infiltrating lymphocytes that act as their killers, suggests that tumor cell cannibalism could be a very direct and efficient way to neutralize immune response, as well. Tumor cell cannibalism may represent a sign of regression to a simpler, ancestral or primeval life style, similar to that of unicellular microorganisms, such as amoebas, where the goal is to survive and propagate in an overcrowded and very hostile microenvironment. In fact, we discovered that metastatic melanoma cells share with amoebas a transmembrane protein TM9SF4, indeed related to the cannibal behavior of these cells. This review attempts to provide a comprehensive description of the current knowledge about the role of TM9SF4 in cancer, highlighting its role as a key player in the cannibal behavior of malignant cancer cells. Moreover, we discuss differences and similarities between tumor cannibalism, entosis, phagocytosis and emperipolesis.

The chaperonin Hsp60 has multiple functions, among which that of supporting the growth of some type of tumours (1). HDACi (histone-deacetylase inhibitors) are drugs that regulate gene expression via modulation of epigenetic mechanisms, and induce tumor-cell death (2). Here, we show that in the tumor cells H292 the HDACi SAHA decreases the intracellular level of Hps60 and promotes its extracellular trafficking by exosomal vesicles. SAHA caused a time- and dose-dependent decrease in cell viability with a G/2M cell-cycle arrest at 24 h and cell death at 48 h. These effects were accompanied by production of reactive oxygen species and mitochondrial membrane-potential dissipation. The marked decrease in Hsp60 level in SAHA-treated cells was not related to proteasomal degradation since it was not affected by the addition of the proteasome inhibitor MG132. Moreover, the analysis of post-translational modifications of Hsp60 revealed that SAHA treatment induced a modest reduction in the ubiquitination of the protein, with no effect on its acetylation state, but did cause a marked increase in tyrosine-nitrated Hsp60. This effect was related to oxidative stress since it was prevented by the anti-oxidant N-acetylcysteine. Most importantly, we showed for the first time that SAHA markedly increases extracellular Hsp60 export via exosomes, which might explain the concomitant decrease of the intracellular chaperonin. Our results suggest that SAHA modifies Hsp60 by nitration and stimulates its extracellular export via exosomes. Since Hsp60-bearing exosomes have been implicated in effective anti-tumour responses, and since elevated intracellular levels of Hsp60 have been related to the arrest of tumour-cell death, our data offer clues to explore what might be as yet uncharacterized mechanisms by which SAHA works as antitumor drug. 1. Rappa et al. (2012) HSP-molecular chaperones in cancer biogenesis and tumour therapy: an overview. Anticancer Res. 32, 5139-5150. 2. Lauricella et al. (2012) SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells. Biochimie 94, 287-299.

BACKGROUND: Heat shock protein 60 (Hsp60) is a chaperonin involved in tumorigenesis, but its participation in tumor development and progression is not well understood and its value as a tumor biomarker has not been fully elucidated. In the current study, the authors presented evidence supporting the theory that Hsp60 has potential as a biomarker as well as a therapeutic target in patients with large bowel cancer. METHODS: The authors studied a population of 97 subjects, including patients and controls. Immunomorphology, Western blot analysis, and quantitative real-time polymerase chain reaction were performed on tissue specimens. Exosomes were isolated from blood and characterized by electron microscopy, biochemical tests, and Western blot analysis. RESULTS: Hsp60 was found to be increased in cancerous tissue, in which it was localized in the tumor cell plasma membrane, and in the interstitium associated with cells of the immune system, in which it was associated with exosomes liberated by tumor cells and, as such, circulated in the blood. An interesting finding was that these parameters returned to normal shortly after tumor removal. CONCLUSIONS: The data from the current study suggested that Hsp60 is a good candidate for theranostics applied to patients with large bowel carcinoma and encourage similar research among patients with other tumors in which Hsp60 has been implicated.

Although limb salvage surgery involving wide resection and limb reconstruction for musculoskeletal sarcomas is well established for low risk of local tumor recurrence, limb function is unsatisfactory for many patients because of the disability in active athletics such as running, jumping, throwing, swimming etc. To avoid poor limb function caused by surgery, it is important to preserve normal nerves, vessels, bones, joints and muscles adjacent to tumor as possible as we can, supported by effective adjuvant therapy to inhibit local tumor recurrence. To develop minimally-invasive limb salvage surgery with minimal damage of normal tissues and low risk of local recurrence, we have recently established a new limb salvage modality of acridine orange (AO) therapy (AOT) based on photodynamic surgery (PDS), photodynamic therapy (PDT) and radiodynamic therapy (RDT) using AO in patients with high-grade malignant musculoskeletal sarcoma. Clinical outcomes of the study showed that: 1) low risk of local recurrence which is almost the same as that with conventional wide resection, and 2) superior limb function to that by wide resection. In this chapter, we present mechanisms of cytocidal effects of AOT based on experimental research and clinical outcome of AOT applied to musculoskeletal sarcoma patients. © 2012 by Nova Science Publishers, Inc. All Rights Reserved.

Integrated in-situ Non-Destructive (ND) ultrasonic techniques and mineral analyses were carried out to assess the conservation state of masonry structures in a monumental building. In this experimental study, in situ measurements of ultrasonic longitudinal pulse velocity with different natural frequency (24-54 kHz) of the transducers were carried out to detect the elasto-mechanical conditions of the building materials. Ultrasonic measurements by surface or indirect transmission (transmitter and receiver along the same face of the investigated masonry wall) were performed using the "step by step" and refraction modalities. These different acquisition modalities were very effective both in detecting the shallow altered areas of the building materials (step by step modality) and in defining the thickness of the alteration (refraction modality). Based on the results of ultrasonic investigations, a sampling was planned in the critical sectors. Optical studies and X-Ray Diffraction (XRD) technique were applied on several microsamples, collected from both mortar and building stones, to determine the mineral composition and intensity of alteration of the materials. The mortar shows three different piled up layers. From the most shallow to deep layers of the mortar, the mineralogy consists of main and accessory primary minerals, and newly-formed minerals. The primary minerals are calcite, quartz, plagioclase, K-feldspar, which occur in different proportion in each mortar level; gypsum and illite occur in different proportion in the different layers, as newly-formed minerals. The building stones are generally limestones, mainly composed by calcite and minor K-feldspar and quartz; gypsum and illite occur in traces. The analysis of the available mineralogical data shows that the most altered zones, independently from type of material, are generally characterized by the presence of gypsum and illite. Mortar and limestone blocks, where lower acoustic velocities were detected, represent the most altered materials. The integrated ultrasonic and mineral analyses show that the alteration phenomena mainly affect the mortar and the shallow part of the limestone blocks, generally waterlogged in the rainy seasons. These phenomena are enhanced not only by mineralogical composition and grain size, but also by the great difference in the elasto-mechanical characteristics among the different layers of the mortar and the shallow part of the stone building materials.