Caspase-independent cell death?

Many cells die with apoptotic morphology and with documented activation of an effector caspase, but there are also many exceptions. Cells frequently display activation of other proteases, including granzymes, lysosomal cathepsins, matrix metalloproteinases, and proteasomal proteases, and others display morphologies that are not fully consistent with classical apoptosis. In some experimental situations, evidence of caspase-dependent death is indirect, demonstrating that the cell can activate caspases rather than that it does. In other situations, such as involution of mammary or prostate tissue, many cells display autophagic or other morphology different from apoptosis, and there is considerable evidence for the activation of a lysosomal system. Prior to total collapse and necrosis, cells that are in trouble can activate numerous physiological pathways toward self-destruction. Intrinsic or extrinsic routes to effector caspase activation are frequently the most rapid and efficient. If neither of these routes is immediately available, owing to mutation, genetic manipulation, inhibitor, or the biology of the cell, other routes may be followed, leading to variant forms of cell death that may display one or more characteristics of apoptosis. Experimental and therapeutic procedures must account for this possibility.     

How does a normal human cell become a cancer cell?

The mechanism by which cells become cancerous has been studied in several different species and cell types. Here, we will focus on the mechanism by which a normal human cell becomes a cancer cell and specifically discuss genes that researchers have used to transform cells. Studying how those genes affect cellular immortalization and transformation will help researchers understand more about cancer biology, find new treatments for cancer and/or improve cell survival during gene therapy.     

Cell–cell and cell–matrix dynamics in intraperitoneal cancer metastasis

The peritoneal metastatic route of cancer dissemination is shared by cancers of the ovary and gastrointestinal tract. Once initiated, peritoneal metastasis typically proceeds rapidly in a feed-forward manner. Several factors contribute to this efficient progression. In peritoneal metastasis, cancer cells exfoliate into the peritoneal fluid and spread locally, transported by peritoneal fluid. Inflammatory cytokines released by tumor and immune cells compromise the protective, anti-adhesive mesothelial cell layer that lines the peritoneal cavity, exposing the underlying extracellular matrix to which cancer cells readily attach. The peritoneum is further rendered receptive to metastatic implantation and growth by myofibroblastic cell behaviors also stimulated by inflammatory cytokines. Individual cancer cells suspended in peritoneal fluid can aggregate to form multicellular spheroids. This cellular arrangement imparts resistance to anoikis, apoptosis, and chemotherapeutics. Emerging evidence indicates that compact spheroid formation is preferentially accomplished by cancer cells with high invasive capacity and contractile behaviors. This review focuses on the pathological alterations to the peritoneum and the properties of cancer cells that in combination drive peritoneal metastasis.     

Hürthle cell carcinoma

Opinion statement Patients with Hürthle cell carcinoma (HCC) of the thyroid often have aggressive tumors and generally have a worse prognosis than those with papillary or follicular thyroid carcinomas [1,2]. A total thyroidectomy with ipsilateral central neck lymphadenectomy and a modified radical neck dissection, if central or lateral nodes are positive, are indicated for HCC. The completeness of this procedure should be assessed by radioiodine scan 3 to 4 months after surgery. Any thyroid remnant should be ablated with radiolabeled iodine 131 to eliminate all tissue at risk and to facilitate the use of serum thyroglobulin in surveillance for tumor recurrence. Fewer than 10% of these cancers take up radioiodine. Recurrent disease is treated surgically with good palliation and appreciable prolongation of life. Local excision and neck dissection for recurrent neck disease or pulmonary wedge resection for lung metastasis has been shown to be effective [3]. All patients with HCC should be given thyroid hormone because most of these tumors have thyrotropin receptors. External beam radiation may be considered for patients with unresectable disease, but this is considered palliative.     

Should extrapulmonary small cell cancer be managed like small cell lung cancer?

BACKGROUND:

The aim of this study was to determine if extrapulmonary small cell carcinomas (EPSCC) should be managed using protocols similar to those for small cell lung cancer (SCLC).

METHODS:

Treatment strategies, survival, patterns of failure, and prognostic factors for patients with EPSCC were analyzed retrospectively at a large cancer center. SCLC was excluded by thoracic computed tomography (75%) or chest radiography (25%).

RESULTS:

Of 120 eligible patients, 70% had limited disease (LD). Treatment modalities included chemotherapy (n = 82; 68%), radiotherapy (RT) (n = 80; 67%), and surgery (n = 41, 34%). The median survival for patients with LD and extensive disease was 1.4 years and 0.7 years, respectively. Gynecologic (n = 31) and gastrointestinal (n = 28) were the most common primary tumor sites. Gynecologic and head and neck primary tumor sites had better 1‐year survival than other sites (P = .019 and 0.005, respectively). Brain metastasis was the site of first distant failure in 4.1% of patients versus 35% for soft tissue metastases. The lifetime risk of brain metastasis was 13%. Definitive RT (P = .004), LD (P = .028), and prophylactic cranial irradiation (PCI) (P = .022) were found to be positive prognostic factors and weight loss (P < .001) was a negative prognostic factor on multivariate analysis.

CONCLUSIONS:

Patients with EPSCC usually experienced short survival, often with early distant metastasis. Although PCI was associated with improved overall survival, brain metastasis was less frequent than in patients with SCLC, and therefore the potential benefit of PCI was less than in patients with SCLC. Definitive chemoradiotherapy was associated with better outcomes and should be delivered whenever feasible. Cancer 2010. © 2010 American Cancer Society.     

Hepatosplenic αβ T cell lymphoma

A 32-year-old male with chronic hepatitis B was admitted to a hospital with cellulitis in the right leg in September 2006. Pancytopenia, hepatosplenomegaly, and systemic superficial lymph node swelling were noted, and he was referred to our hospital. He developed fever and liver dysfunction in June 2007 and underwent a splenectomy. His pancytopenia subsequently improved. A pathologic diagnosis of hepatosplenic αβ T cell lymphoma was made by examining spleen tissue and biopsy specimens of the liver and mesenteric lymph node. He had stage IVB disease because neoplastic T cells were noted in the bone marrow. The response of the lymphoma to conventional chemotherapy including the CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) and DeVIC (dexamethasone, etoposide, ifoshamide, carboplatin) regimens was poor and transient. A partial remission was obtained with an ESHAP (etoposide, cisplatin, cytarabine, methylprednisolone) regimen. Therefore, we planned a bone marrow transplantation (BMT) from an HLA-haploidentical sibling donor. He was moved to the Department of Hematology, Hyogo Medical College, to receive this BMT as part of a clinical trial. During the conditioning procedure for the transplantation, however, he died of septicemia. Since hepatosplenic αβ T cell lymphoma is very rare with only 23 reported cases to date, herein we report this case and discuss the therapeutic strategy.     

Irradiation enhances dendritic cell potential antitumor activity by inducing tumor cell expressing TNF-α

Dendritic cells (DCs)-based tumor vaccines have shown to be the promising methods for inducing therapeutic antitumor response. However, DCs alone rarely carry curative antitumor activity, and the immunosuppressive microenvironment may contribute to this defect of DC vaccinal function. Irradiation in combination with DCs has been shown to promote immune-mediated tumor destruction in preclinical studies. However, little is known about how irradiation alters the tumor microenvironment, and what host pathways modulate the activity of administrated DCs. In this study, BALB/c mice and the 4T1 breast cancer cell line were used in a tumor-bearing model. The tumor-bearing mice were irradiated locally up to 10 Gy for 3 consecutive days or a single dose of 30 Gy using a cesium source. Studies of dynamic change of the tumor microenvironment in irradiated versus untreated tumors revealed that there was no obvious change on IL-10, IL-6 and TGF-β expression or production, whereas increased TNF-α level within the first 2 weeks of irradiation. The increased TNF-α level is exactly right timing window for DCs injection, corresponding to the significant elevation of intratumoral CD8⁺ T infiltration and the regression of tumor size. With attention to scheduling, combination X-ray with DCs i.t. injection may offer a practical strategy to improve treatment outcomes.     

Allogeneic stem cell transplantation for mantle cell lymphoma--does it deserve a better look?

Mantle cell lymphoma is a subtype of non-Hodgkin's lymphoma. Mantle cell is generally considered incurable with a median overall survival of about 3 years. It is most common in 50 - 70 year old individuals and for this reason transplantation is not a common therapeutic option. Autologous stem cell transplantation does not appear to improve survival with most patients relapsing after transplant and no disease-free plateau. We present 6 mantle cell patients that had a mean of 3 different types of therapy prior to allogeneic transplantation. Allogeneic transplantation is associated with substantial mortality post-transplant from acute toxicity and GVHD. Despite the extensive amount of pretransplant therapy in our patient population, there was no transplant related mortality. All patients are alive and in remission a median of 4.3 plus years after transplantation. Survival from the date of diagnosis is a median of 6.5 plus years. The results of this series would suggest that in a selected group of patients allogeneic stem cell transplantation may be the treatment of choice for lymphomas not curable by standard therapy or autotransplant.     

Livin mediates tumor cell invasion in the DU-145 cell line via NF-κB

Livin is a member of the family of inhibitors of apoptosis proteins (IAPs) and tumor cell invasion is a general property of multiple IAPs. Livin is highly expressed in prostate cancer (PCa) tissues. Livin overexpressing cells are more resistant to apoptotic stimuli than normal cells. Thus, aberrantly increased cell survival is an invariable requirement of metastasis. In this study, we investigated whether livin signaling affects metastasis by transfecting siRNA targeting livin into the DU-145 prostate cancer cell line to confirm the anti-invasion effect and blockade of the livin gene. We found that livin knockdown inhibited DU-145 prostate carcinoma cell invasion. We investigated how livin promotes tumor cell invasion, and found that livin induction of fibronectin contributed to tumor cell invasion. In addition, we found that livin induction of fibronectin regulates tumor cell invasion via nuclear factor κB (NF-κB) signaling. These data showed that livin, as a gene directly promoting metastasis, can be useful for therapeutic intervention against advanced and disseminated PCa.     

Activated leukocyte cell adhesion molecule (ALCAM/CD166): Signaling at the divide of melanoma cell clustering and cell migration?

Orchestrated modulation of cell adhesion is essential for development and homeostasis in multicellular organisms. It optimizes embedding of the cell in its dynamic environment and facilitates appropriate cell responses and intercellular communication. Chronic disturbance of this delicate equilibrium causes defects in tissue architecture and sometimes cancer. In tumor cell biology, dynamic control of adhesion molecules is important to proceed through the metastatic cascade and to allow cell release from the primary tumor, invasion of the surrounding matrix, intravasation and adhesion to vascular endothelial cells to facilitate extravasation. Intertwined and multiple adhesive interactions rather than individual interactions presumably play critical roles in neoplastic development. Yet, knowledge of the contribution of each individual adhesion molecule is essential to unravel this network of interactions. This review will focus on activated leukocyte cell adhesion molecule (ALCAM/CD166) and its role in human melanoma progression. It is hypothesized that ALCAM may function as a cell surface sensor to register local growth saturation and to regulate cellular signaling and dynamic responses.     

Intravascular large B‑cell lymphoma

Intravascular lymphoma (IVL), a rare, extranodal form of non-Hodgkin lymphoma (NHL), can cause infarcts by occluding small arteries of the brain. Owing to its heterogeneous clinical manifestations and unfavorable prognosis, the diagnosis is often made postmortem. Patients can present with a range of motor or sensory deficits, rapid cognitive impairment, aphasia or signs of myelitis, often with nonspecific radiographic findings.Timely recognition of a treatable disease is essential to prevent permanent neurocognitive defects. We present a case who could be treated successfully with chemotherapy.     

Why do B cell lymphoma fail to elicit clinically sufficient T cell immune responses?

There is no doubt that human B cell lymphoma does not elicit a clinically sufficient T cell mediated immune response that results in tumor rejection. However, the mechanisms leading to this lack of T cell recognition and effector function are still not fully understood. Many potential mechanisms such as "ignorance" including "antigen silencing", "tolerance" including "infectious tolerance" and "anergy" or "immunosuppression" have been identified in different model systems and all these could, in part, account for the lack of immune recognition in B cell lymphoma. Malignant B cells are poor antigen presenting cells and T cells in close proximity to the malignant cells are hyporesponsive with detects in T cell receptor signaling and cytotoxic effector function. This review will discuss recent in vitro findings in context of in vivo data in murine model systems relevant to B cell lymphoma. Understanding these complex defects of anti-lymphoma immune responses should allow us to redefine our immunotherapeutic strategies to overcome these detects and induce clinically sufficient T cell mediated immune responses.