Does tumor growth follow a "universal law"?

A general model for the ontogenetic growth of living organisms has been recently proposed. Here we investigate the extension of this model to the growth of solid malignant tumors. A variety of in vitro and in vivo data are analysed and compared with the prediction of a "universal" law, relating properly rescaled tumor masses and tumor growth times. The results support the notion that tumor growth follows such a universal law. Several important implications of this finding are discussed, including its relevance for tumor metastasis and recurrence, cell turnover rates, angiogenesis and invasion.     

Serum tumor markers in bile duct cancer – a review

Abstract

Context: Bile duct cancer (BDC) is a disease with a very grave prognosis, often diagnosed too late.

Objective: The aim of this review is to evaluate available literature on tumor markers in serum from patients with BDC.

Methods: Using the search words “serum markers”, “bile duct cancer”, “cholangiocarcinoma”, “biomarker” and “tumor marker”, a search was carried out.

Results: Seventy-five studies were included in the review.

Conclusion: CA19-9 is by far the most studied and most promising diagnostic and/or prognostic marker in BDC. But also the different mucins are interesting as new markers of BDC in serum.     

α-Enolase: a promising therapeutic and diagnostic tumor target

α-enolase (ENOA) is a metabolic enzyme involved in the synthesis of pyruvate. It also acts as a plasminogen receptor and thus mediates activation of plasmin and extracellular matrix degradation. In tumor cells, ΕΝΟΑ is upregulated and supports anaerobic proliferation (Warburg effect), it is expressed at the cell surface, where it promotes cancer invasion, and is subjected to a specific array of post-translational modifications, namely acetylation, methylation and phosphorylation. Both ENOA overexpression and its post-translational modifications could be of diagnostic and prognostic value in cancer. This review will discuss recent information on the biochemical, proteomics and immunological characterization of ENOA, particularly its ability to trigger a specific humoral and cellular immune response. In our opinion, this information can pave the way for effective new therapeutic and diagnostic strategies to counteract the growth of the most aggressive human disease.     

T cell–tumor cell: a fatal interaction?

Fas (Apo-1/CD95) is a cell-surface protein that is responsible for initiating a cascade of proteases (caspases) culminating in apoptotic cell death in a variety of cell types. The function of the Fas/FasL system in the dampening of immune responses to infectious agents through the autocrine deletion of activated T cells has been well documented. More recently, it has been proposed that tumor cells express FasL, presumably to avoid immune detection. In this review, we focus on the role of the interaction of Fas and FasL in the modulation of antitumor responses. We critically examine the evidence that FasL is expressed by tumor cells and explore alternative explanations for the observed phenomena in vitro and in vivo. By reviewing data that we have generated in our laboratory as well as reports from the literature, we will argue that the Fas/FasL system is a generalized mechanism used in an autocrine fashion to regulate cell survival and expansion in response to environmental and cellular cues. We propose that FasL expression by tumor cells, when present, is indicative of a perturbed balance in the control of proliferation while “immune privilege” is established by “suicide” of activated antitumor T cells, a form of activation-induced cell death. Received: 5 May 1998 / Accepted: 20 May 1998     

Right atrial tumor: a contraindication to minimally invasive surgery?

Cardiac tumors are rarely observed. The incidence of primary cardiac tumors in autopsy series ranges from 0.0017% to 0.19%. Surgical resection is the main therapy for the majority of the cardiac tumors. Surgical treatment of these tumors carries an operative mortality rate of 3% or less. In this article, we present our experience with a female patient, who had a right sided atrial tumor mimicking a myxoma. Port access surgery was performed through a small right sided "key-hole" working port in the fourth intercostal space. Extracorporeal circulation was conducted by femoro-femoral bypass and a kinetic assisted venous drainage system. Although, the safety and efficacy of port access approach have been well documented for resection of left atrial tumors in some series, use of this technique for right atrial tumor resection can be detrimental.     

Interleukin 12: still a promising candidate for tumor immunotherapy?

Interleukin 12 (IL-12) seemed to represent the ideal candidate for tumor immunotherapy, due to its ability to activate both innate (NK cells) and adaptive (cytotoxic T lymphocytes) immunities. However, despite encouraging results in animal models, very modest antitumor effects of IL-12 in early clinical trials, often accompanied by unacceptable levels of adverse events, markedly dampened  hopes of the successful use of this cytokine in cancer patients. Recently, several clinical studies have been initiated in which IL-12 is applied as an adjuvant in cancer vaccines, in gene therapy including locoregional injections of IL-12 plasmid and in the form of tumor-targeting immunocytokines (IL-12 fused to monoclonal antibodies). The near future will show whether this renewed interest in the use of IL-12 in oncology will result in meaningful therapeutic effects in a select group of cancer patients.     

Does a targeting ligand influence nanoparticle tumor localization or uptake?

Inclusion of a tumor-targeting molecule in nanosized delivery systems increases their in vivo efficacy. However, the biodistribution and pharmacokinetics of the uptake of such particles have not yet been well addressed. Several recent papers have suggested that tumor-targeting ligands function primarily to increase intracellular uptake of the nanocomplex and do not influence tumor localization. However, other reports indicate that they do play a role in the accumulation in the tumor. One difference might be the presence or absence of poly-[ethylene glycol] (PEG) in the complex and its impact on the enhanced permeability and retention (EPR) effect. Further studies are clearly needed to more fully elucidate the influence of composition on tumor-targeted, systemic delivery of nanoparticles.     

Antitumor vaccines: is it possible to prevent a tumor?

The main medical use of vaccines is to induce a state of immunity in healthy individuals to protect them from deadly or dangerous diseases. In the field of cancer immunology, however, vaccines are being used in patients as therapy, often with a very poor success rate against advanced disease. This paper reviews recent preclinical evidence in favor of the prophylactic use of immunological approaches to cancer. Successful attempts at immunological cancer prevention in HER-2/neu transgenic mice are described as an example. The specific properties of the HER-2/neu gene product as a tumor antigen, and the nature of the immune responses induced by effective preventive treatments are reviewed. Although the very high rate of mammary carcinoma prevention in mice has generated enthusiasm, it should not be forgotten that such treatments, when administered to healthy humans at risk of cancer, may carry the risk of inducing autoimmunity. These issues can be addressed in preclinical studies in appropriate animal models.     

Masson’s tumor of the kidney: a case report

Background

Intravascular papillary endothelial hyperplasia (known also as Masson’s tumor) is a benign vascular lesion that commonly occurs in the skin and is rarely found in solid organs, especially in the kidney. In what follows, we will look into the first case of an unexpectedly diagnosed Masson’s tumor of the kidney presenting as a suspicious renal cyst.

Case presentation

A 61-year-old Arab man presented with a left renal cyst, incidentally revealed by ultrasonography. The laboratory values were unremarkable. Computed tomography and magnetic resonance imaging demonstrated a 38 mm left renal midportion Bosniak IV cyst. Our patient underwent a radical nephrectomy. Histopathology revealed the diagnosis of intravascular papillary endothelial hyperplasia. There was no recurrence detected after 9 years of follow-up.

Conclusions

Renal intravascular papillary endothelial hyperplasia is a rare benign tumor which can mimic a suspicious renal mass on radiological findings. Thus, this entity should be considered more often in the thick of the diagnostic possibilities in order to avoid unnecessary nephrectomies.

     

NF-κB potentiates tumor growth by suppressing a novel target LPTS

Background

Chronic inflammation is causally linked to the carcinogenesis and progression of most solid tumors. LPTS is a well-identified tumor suppressor by inhibiting telomerase activity and cancer cell growth. However, whether and how LPTS is regulated by inflammation signaling is still incompletely elucidated.

Methods

Real-time PCR and western blotting were used to determine the expression of p65 and LPTS. Reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation were performed to decipher the regulatory mechanism between p65 and LPTS. Cell counting kit-8 assays and xenograt models were used to detect p65-LPTS-regulated cancer cell growth in vitro and in vivo, respectively.

Results

Here we for the first time demonstrated that NF-κB could inhibit LPTS expression in the mRNA and protein levels in multiple cancer cells (e.g. cervical cancer and colon cancer cells). Mechanistically, NF-κB p65 could bind to two consensus response elements locating at ?1143/?1136 and ?888/?881 in the promoter region of human LPTS gene according to EMSA and ChIP assays. Mutation of those two binding sites rescued p65-suppressed LPTS promoter activity. Functionally, NF-κB regulated LPTS-dependent cell growth of cervical and colon cancers in vitro and in xenograft models. In translation studies, we verified that increased p65 expression was associated with decreased LPTS level in multiple solid cancers.

Conclusions

Taken together, we revealed that NF-κB p65 potentiated tumor growth via suppressing a novel target LPTS. Modulation of NF-κB-LPTS axis represented a potential strategy for treatment of those inflammation-associated malignancies.

     

DA-Raf,a dominant-negative antagonist of the Ras–ERK pathway,is a putative tumor suppressor

Activating mutations of RAS genes, particularly KRAS, are detected with high frequency in human tumors. Mutated Ras proteins constitutively activate the ERK pathway (Raf–MEK–ERK phosphorylation cascade), leading to cellular transformation and tumorigenesis. DA-Raf1 (DA-Raf) is a splicing variant of A-Raf and contains the Ras-binding domain (RBD) but lacks the kinase domain. Accordingly, DA-Raf antagonizes the Ras–ERK pathway in a dominant-negative fashion and suppresses constitutively activated K-Ras-induced cellular transformation. Thus, we have addressed whether DA-Raf serves as a tumor suppressor of Ras-induced tumorigenesis. DA-Raf(R52Q), which is generated from a single nucleotide polymorphism (SNP) in the RBD, and DA-Raf(R52W), a mutant detected in a lung cancer, neither bound to active K-Ras nor interfered with the activation of the ERK pathway. They were incapable of suppressing activated K-Ras-induced cellular transformation and tumorigenesis in mice, in which K-Ras-transformed cells were transplanted. Furthermore, although DA-Raf was highly expressed in lung alveolar epithelial type 2 (AE2) cells, its expression was silenced in AE2-derived lung adenocarcinoma cell lines with oncogenic KRAS mutations. These results suggest that DA-Raf represents a tumor suppressor protein against Ras-induced tumorigenesis.     

ErbB2 and TGF-beta: a cooperative role in mammary tumor progression?

Amplification and overexpression of ErbB2 (HER2/Neu) is one of the most common alterations associated with breast cancer. Activation of ErbB2 via homodimerization in a non-transformed human mammary epithelial cell line, MCF-10A, in basement membrane cultures leads to formation of proliferative structures that share properties with non-invasive early stage lesions. Recently, we have shown that activation of ErbB2 homodimers combined with expression of transforming growth factor (TGF)-beta induces invasive and migratory activity in MCF-10A cells. In this system, migration requires inputs from numerous cellular pathways. We discuss this data and a model for migration induced by ErbB2 and TGF-beta. Concurrent studies by other groups have also shown that ErbB2 and TGF-beta can cooperate to increase metastatic and invasive behavior in murine mammary tumors. Here we discuss these studies and the potential implications of this research on breast cancer therapeutics.     

Optimal response to chemotherapy for a mathematical model of tumor–immune dynamics

An optimal control problem for cancer chemotherapy is considered that includes immunological activity. In the objective a weighted average of several quantities that describe the effectiveness of treatment is minimized. These terms include (i) the number of cancer cells at the terminal time, (ii) a measure for the immunocompetent cell densities at the terminal point (included as a negative term), (iii) the overall amount of cytotoxic agents given as a measure for the side effects of treatment and (iv) a small penalty on the terminal time that limits the overall therapy horizon which is assumed to be free. This last term is essential in obtaining a well-posed problem formulation. Employing a Gompertzian growth model for the cancer cells, for various scenarios optimal controls and corresponding responses of the system are calculated. Solutions initially follow a full dose treatment, but then at one point switch to a singular regimen that only applies partial dosages. This structure is consistent with protocols that apply an initial burst to reduce the tumor volume and then maintain a small volume through lower dosages. Optimal controls end with either a prolonged period of no dose treatment or, in a small number of scenarios, this no dose interval is still followed by one more short burst of full dose treatment.