Vascular permeability in malignant disease

Summary Experimental demonstration that vessels draining large tumours are impermeable to cellular elements. Thus the pulmonary vessels of animals bearing large, primary (other than gastro-intestinal) cancers can become impermeable to tumour emboli. This imperviousness prevents the establishment of secondaries in the lung and promotes the transpulmonary passage of tumor cells. This phenomenon may account for the development of paradoxical metastases.     

Cancer and blood coagulation

In human patients, blood coagulation disorders often associate with cancer, even in its early stages. Recently, in vitro and in vivo experimental models have shown that oncogene expression, or inactivation of tumour suppressor genes, upregulate genes that control blood coagulation. These studies suggest that activation of blood clotting, leading to peritumoral fibrin deposition, is instrumental in cancer development. Fibrin can indeed build up a provisional matrix, supporting the invasive growth of neoplastic tissues and blood vessels. Interference with blood coagulation can thus be considered as part of a multifaceted therapeutic approach to cancer. Received 30 November 2005; received after revision 7 February 2005; accepted 8 February 2006     

The role of chemokines and their receptors in angiogenesis

Chemokines are a vertebrate-specific group of small molecules that regulate cell migration and behaviour in diverse contexts. So far, around 50 chemokines have been identified in humans, which bind to 18 different chemokine receptors. These are members of the seven-transmembrane receptor family. Initially, chemokines were identified as modulators of the immune response. Subsequently, they were also shown to regulate cell migration during embryonic development. Here, we discuss the influence of chemokines and their receptors on angiogenesis, or the formation of new blood vessels. We highlight recent advances in our understanding of how chemokine signalling might directly influence endothelial cell migration. We furthermore examine the contributions of chemokine signalling in immune cells during this process. Finally, we explore possible implications for disease settings, such as chronic inflammation and tumour progression.     

The in vitro effect of aprotinin upon spleen cells from normal and tumour-bearing mice exposed to PPD and tumour cells

Aprotinin (Trasylol) is shown to enhance the response of spleen cells from normal and tumour bearing mice to PPD nd tumour cells. This enhancement is greater in the tumour-bearing mice.     

Survival of tumor fragments as a function of temperature: correlation with electric impedance]

The ability of small pieces of Rat Walker's tumour carcinome 256 to develop a subcutaneous tumour on another Rat is dependent on the value and the duration of heat treatment.     

Common Molecular Mechanisms of Mammary Gland Development and Breast Cancer

The mammary gland undergoes major developmental changes during puberty and pregnancy. It is thought that stem cells drive mammary gland development during puberty and are responsible for tissue maintenance as well as the major growth and remodelling that occurs with every pregnancy. The use of sophisticated cell separation procedures has facilitated the prospective isolation of mammary epithelial stem and differentiated cell subpopulations from the mouse mammary gland, while studies of primary human breast cancers have described sub-populations of tumourigenic cells capable of initiating tumour growth in immuno-compromised mice. These potential tumour 'stem cells' constitute an important therapeutic target population with respect to cancer therapy, as these are likely to be the cells which maintain tumour growth. Understanding the origin of these cells, their relationship to breast cancer subtypes, and how and why they differ from normal breast stem cells will lead to a revolution in tumour understanding, treatment and prevention. (Part of a Multi-author Review).     

Redefining tumour suppressor genes: exceptions to the two-hit hypothesis

Knudsons two-hit model of tumour suppressor genes supposes that two mutations are required to cause a tumour, one occurring in each of the two alleles of the gene. Many such cancer genes exhibiting biallelic disruption and truncating point mutations have been identified, revealing the success of the model. Despite changes in our concept of cancer genes, two inactivating point mutations are still considered the hallmark of tumour suppressor genes. Recently, however, more and more reports describe candidate tumour suppressors that do not conform to this standard definition, including haploinsufficient genes requiring inactivation of only one allele, and genes inactivated not by mutation but rather epigenetic hypermethylation. This review describes some of these exceptions and proposes a revised tumour suppressor gene definition to facilitate the identification of this new generation of tumour suppressor loci.Received 21 January 2003; received after revision 26 March 2003; accepted 1 April 2003     

Activation of cytotoxic T cells by solid tumours?

Tumour-specific cytotoxic T cells (CTLs) are among the best-defined biological anticancer weapons. Nevertheless, they often fail to control tumour growth in vivo. Many reasons for this have been evoked tumours may actively inhibit CTLs, or may protect them selves from CTL recognition by various means. However, one does not necessarily need to postulate such active immune evasion mechanisms specifically acquired by tumour cells. In this review we argue that the failure of immune protection is due to the intrinsic inability of tumours to activate an effective immune response, and that many tumours are similar to normal issues in this respect. It is striking to see that the majority of the so-called immune escape mechanisms are not specifically acquired by selected tumour cells, but are common mechanisms shared between solid tumours and normal, healthy tissues. Immune responses are poor because tumour antigens do not efficiently localize to lymph follicles in lymphoid tissues, and are not efficiently presented to CTLs in an immunogenic context. The fact that tumours do not induce CTLs but are often susceptible to lymphocyte-mediated cytotoxicity indicates that more intensified immunization protocols should result in improved clinical outcome.     

The in vitro effect of aprotinin upon spleen cells from normal and tumour-bearing mice exposed to PPD and tumour cells

Summary A protinin (Trasylol) is shown to enhance the response of spleen cells from normal and tumour bearing mice to PPD and tumour cells. This enhancement is greater in the tumour-bearing mice.Acknowledgments. We are grateful to Bayer (U.K.) Limited for generous supplies of aprotinin. The PPD was supplied by the Ministry of Agriculture. The work was supported by a grant from the North of England Cancer Research Campaign.     

Peritoneal macrophages from adjuvant arthritic rats enhance tumour cell growth in vitro.

Peritoneal macrophages from rats with adjuvant arthritis enhance the incorporation of 3H-thymidine in 2 tumour cell lines in vitro. Maximal enhancement is found during the development of the secondary lesions, and it is suggested that the immunologic commitment of the macrophages could interfere with their regulation of tumour cell proliferation in vivo.     

Peritoneal macrophages from adjuvant arthritic rats enhance tumour cell growth in vitro

Summary Peritoneal macrophages from rats with adjuvant arthritis enhance the incorporation of³H-thymidine in 2 tumour cell lines in vitro. Maximal enhancement is found during the development of the secondary lesions, and it is suggested that the immunologic commitment of the macrophages could interfere with their regulation of tumour cell proliferation in vivo.Acknowledgments. The authors thank Drs P.F. Engel and M.P. Andreasen from the Finsen Institute, Copenhagen, for their gift of tumour cells and Ms E. Greve Petersen, Ms B. Hasselriis and Ms F. Norris for excellent technical assistance.     

Alzheimer’s disease and CADASIL are heritable,adult-onset dementias that both involve damaged small blood vessels

This essay explores an alternative pathway to Alzheimer’s dementia that focuses on damage to small blood vessels rather than late-stage toxic amyloid deposits as the primary pathogenic mechanism that leads to irreversible dementia. While the end-stage pathology of AD is well known, the pathogenic processes that lead to disease are often assumed to be due to toxic amyloid peptides that act on neurons, leading to neuronal dysfunction and eventually neuronal cell death. Speculations as to what initiates the pathogenic cascade have included toxic abeta peptide aggregates, oxidative damage, and inflammation, but none explain why neurons die. Recent high-resolution NMR studies of living patients show that lesions in white matter regions of the brain precede the appearance of amyloid deposits and are correlated with damaged small blood vessels. To appreciate the pathogenic potential of damaged small blood vessels in the brain, it is useful to consider the clinical course and the pathogenesis of CADASIL, a heritable arteriopathy that leads to damaged small blood vessels and irreversible dementia. CADASIL is strikingly similar to early onset AD in that it is caused by germ line mutations in NOTCH 3 that generate toxic protein aggregates similar to those attributed to mutant forms of the amyloid precursor protein and presenilin genes. Since NOTCH 3 mutants clearly damage small blood vessels of white matter regions of the brain that lead to dementia, we speculate that both forms of dementia may have a similar pathogenesis, which is to cause ischemic damage by blocking blood flow or by impeding the removal of toxic protein aggregates by retrograde vascular clearance mechanisms.     

Recent insights into the role of integrins in cancer metastasis

Integrins have been repeatedly found involved in cancer metastasis. The past two years have seen considerable evolution in our knowledge on the role of these integrins in tumour cells. This includes the elucidation of different signalling pathways by which integrins dictate the anchorage-independent growth, survival and motility of tumour cells. Moreover, integrins may have a more complex role in cancer metastasis as they cooperate with serine proteases and metalloproteases to promote tumour cell invasion and angiogenesis. Finally, integrins favour tumor cell extravasation.     

Common Molecular Mechanisms of Mammary Gland Development and Breast Cancer

Hypoxia affects many important processes in tumour progression and is a key feature in the tumour microenvironment that needs to be taken into account when evaluating prognostics and therapeutic options for cancer patients. Hypoxia-regulating proteins, i.e. hypoxia inducible factors (HIFs), and associated gene products have been linked to certain tumour behaviours and might be useful as prognostic and predictive markers. Recently, hypoxia-driven gene products have been launched as novel cancer treatment targets with the potential to increase tumour-specific effects. Breast cancer consists of a multitude of different diseases with certain common characteristics, but also clearly disparate behaviours and genetic alterations. In this review we will summarise the role of hypoxia in breast cancer and specifically outline the importance of hypoxia and HIF-1alpha regarding prognostic and treatment-specific implications. (Part of a Multi-author Review).     

Prostaglandin-like substances inPropionibacterium acnes. IV. Effect on isolated human vessels

Summary The present study demonstrates a powerful vasoconstrictor activity of prostaglandin-like substances (PLS), extracted fromP. acnes, on human blood vessels. PLS is about equipotent to PGE₂ in its effect on human umbilical vessels, but the contractile response pattern is different. PLS therefore seems to have specific and different physiological characteristics.     

Changes in immune reactivity during growth of an adenovirus 12-induced transplantable tumour in CBA mice

Summary Early suppression, followed by a period of enhancement and finally, suppression, was seen when the spleen cell response to T and B cell mitogens was monitored during growth of an adenovirus 12-induced tumour in CBA black mice. The macrophage content of the tumour changed with time and these fluctuations correlated with the ability of tumour tissue extracts to enhance the normal spleen cell response to mitogen.Acknowledgments. Thanks are dur to the Yorkshire Cancer Research Campaign, and the Cancer Research Committee of Sheffield University for financial support, also to Professor C.W. Potter for advice.     

Effect of synthetic polynucleotides on the growth of transplantable tumours in BALB/c mice.

The effect of BALB/c mice pretreatment with tumour cells (a mammary adenocarcinoma, ADK-1t and an IgA secreting plasmocytoma, MOPC-315) adsorbed with poly I:C, poly I and poly C is examined. Only mice pretreated with cells of both tumours adsorbed with poly I:C and poly C proved to be extensively protected against challenge by homologous untreated tumour cells, whereas this was not so in the case of poly I. A possible explanation of this phenomenon is discussed.     

Adenosine-5'-triphosphate levels in experimental CaNT and Fib/t tumours of varying volume and degree of hypoxia

The variation of adenosine-5'-triphosphate (ATP) content per unit mass of tumour, versus tumour volume was measured in vivo under normoxic conditions, using CaNT and Fib/t murine tumours grown in CBA and WHT mice respectively. A monotonically decreasing relation was found. Artificially induced tumour hypoxia resulting from 15 min of clamping was accompanied by reduced ATP levels.     

Spécificité de l'antigène tumoral décelé dans le foie de rat porteur d'une tumeur de Walker

Summary By means of systematic comparative immunoelectrophoretic analysis, it has been shown that the antigenic material appearing in the liver of a Walker tumour bearing rat is highly specific to the tumour. In fact we have been unable to detect such an antigen either in embryonic neonatal, regenerating or in the liver of acute inflammations bearing rats.

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Travail subventionné par l'Institut du Cancer du Canada.