Cancer

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Haim Cohen, Ph.D
Department of Pathology,
Harvard Medical School,
Boston, MA

The incidence of cancer increases as we age: during the last decade of life, the risk of developing cancer is a startling 50% for men and 33% for women.¹ What is the underlying link between aging and cancer? This link may be found by investigating diseases that are associated with both a high frequency of cancer and premature signs of aging. Such diseases, known collectively as RecQ syndromes, are caused by mutations in genes encoding RecQ-like proteins.² The RecQ family of proteins has a high degree of homology to the helicase domain of the RecQ helicase of E. coli. The helicase region is required for all RecQ helicases to unwind duplex DNA from 3' to 5' direction in vitro; however, the in vivo function of the eukaryotic RecQ is unknown.

At least three inherited human diseases are caused by mutations in RecQ-like genes: Werner syndrome (WS), Bloom syndrome (BS), and Rothmund-Thomson syndrome (RTS).³ These diseases share two main features: premature aging and a high level of genomic instability that manifests itself as a high incidence of cancer.

The hallmark of Bloom syndrome is an increased level of sister chromatid exchange, and patients present with sun-sensitive skin pigmentation and a predisposition to certain malignancies.

Dr. Christine I. Chen, MD, FRCPC
Princess Margaret Hospital,
University Health Network,
Toronto, ON

Introduction
Multiple myeloma arises from a malignancy of plasma cells in the bone marrow which typically produce an immunoglobulin, also referred to as a monoclonal protein (M-protein), that is detectable in the patient's blood and/or urine. Myeloma is not a common disease (incidence of 1400/year in Canada), typically affecting older individuals (median age 65 years). It is more common in blacks and slightly more prevalent in males. Since myeloma is a relatively slow-growing malignancy, many patients will have the disease for months or even years before a diagnosis is made and may continue to follow an indolent course. The pathogenesis of the disease is poorly understood.

Clinical Features
Characteristic clinical features of multiple myeloma are anemia, renal failure, bony lesions with pathologic fractures and associated pain, hypercalcemia, and recurrent infections (See Table 1). Many patients, however, will present with asymptomatic anemia or a monoclonal gammopathy, which is usually discovered during incidental lab testing.

A new technique has been designed that will hopefully aid physicians in detecting the early stages of bladder cancer. Researchers at Yale University have developed a urine test that identifies a protein that is found in bladder cancer cells.

Currently, the methods for the detection of bladder cancer rely on cytological examination of urine and a cytoscopy, where a scope is passed through the urethra into the bladder to examine the bladder walls. The cytoscopy is both expensive and painful for the patient. In a study of 158 patients, the group found that all patients with new or recurring bladder cancer tested positive for the presence of the protein survivin in their urine. All healthy patients tested negative for the protein and patients with other cancers including kidney, prostate, cervical and vaginal cancer also all tested negative for survivin.

The survival rate for bladder cancer is quite high, with a five-year survival rate of 93%. However, most patients will have a recurrence of the disease, and once diagnosed and treated, patients must undergo a cytoscopy every three months for two years to ensure that the cancer has not returned. In addition, they must have an annual upper tract study where the kidneys, urethra and bladder are examined for the presence of malignant cells.

Several other studies have investigated a marker to detect bladder cancer, and until now telomerase has been the new marker. Until a method is developed that is 100% specific and sensitive, cytoscopy will remain the only reliable method to test for bladder cancer.

People over the age of 40 are at a higher risk for bladder cancer, and men are at higher risk than are women. There is also an increased rate of this cancer in smokers when compared to non-smokers. For a full article on the diagnosis and treatment of bladder cancer in the elderly, please see next month's issue of Geriatrics & Aging.

Source

Smith, SD et al. Urine detection of survivin and diagnosis of bladder cancer. JAMA 2001; 285:324-328.

Anna Liachenko, BSc, MSc
Managing Editor,
Geriatrics & Aging

The relationship between aging and cancer has its basis in cell cycle alterations. While multiple factors affect cell cycle progression, recent research has directed a great deal of attention to telomere length as a key factor affecting mammalian cell proliferation. This article discusses recent findings with respect to the role of telomeres and telomerase in cancer, cellular aging, and longevity.

Telomeres are short DNA repeats located at the ends of eukaryotic chromosomes. Telomeres cap chromosomal ends preventing the loss of important genes during cell division. With every cell division, the length of telomeres decreases unless it is corrected by telomerase, a ribonucleoprotein enzyme that extends the telomeres by adding hexameric nucleotide repeats to the ends of chromosomes. In humans, telomeres are short, and telomerase activity is low in many somatic tissues but is present in germ cells, activated leukocytes, and stem cells from a variety of organs. The study of telomeres has been hampered by the fact that classical animal models, such as mice, have highly active telomerase. This results in long telomeres that do not shorten enough during the animal lifespan to play a significant role in cellular aging. Recently, a genetically altered telomerase-deficient mouse model has been created by a group of researchers at Harvard.

A major study by the research group of Dr. Josef Penninger, at the University of Toronto, has identified a protein that, when absent, appears to contribute to the development of colorectal cancer. The protein in question is the p110g catalytic subunit of phosphoinositide-3-OH kinases (PI(3)Ks), a family of proteins that regulate a vast array of fundamental cell responses, including proliferation, transformation, differentiation and protection from apoptosis. Quite by accident, the researchers discovered that genetic inactivation of the p110g subunit leads to the development of invasive colorectal carcinomas in mice. In humans it has been previously found that p110g protein expression is lost in primary colorectal adenocarcinomas and in colon cancer cell lines. Overexpressing wildtype or kinase-dead p110g in human colon cancer cell lines with mutations of tumour suppressors, or with the oncogenes b-catenin and Ki-ras, suppressed tumorigenesis.

Penninger's group was examining genetically altered mice to determine how their white blood cells responded to infection when the mice lost weight, became sick and began to die. It turned out that they were riddled with colon cancer. Turning this discovery into practical medicine for the treatment of colon cancer in humans will obviously require time and a lot more study. However, it is hoped that this knowledge may help in the design of novel strategies for fighting colon cancer.

Colon cancers are the second leading cause of cancer death and it is estimated that 50% of humans develop colon tumours by the age of 70.

Source

Sasaki T, et al. Colorectal Carcinomas in Mice Lacking the Catalytic Subunit of PI(3)Kg Nature 2000 (406) 897-902.

Rachel L. Panton¹,
Catharine Ramsey, Brenda L. Gallie^1,2,3
¹Department of Ophthalmology,
²The Hospital for Sick Children; Cancer Informatics, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network;
³Departments of Ophthalmology and Molecular and Medical Genetics, University of Toronto.

Only as a grandmother, did Catharine Ramsey learn what had caused the loss of her eye in infancy, information that was to change the life of her entire family.

"I was born on January 19, 1939, adopted as an infant and raised in Kirkland Lake, Ontario. On September 26, 1940 my left eye was removed due to 'eye problems'. Throughout my life, I was told 'you were sick when you were a baby and had to have your eye out!'

I often asked my ophthalmologist why this had happened to me, but I did not receive any clear answers. When my daughter Margaret married, I asked again if there was any information I needed to pass along to my children. I was told that there wasn't any.

My beautiful granddaughter, Jennifer, was born November 6, 1988. She was perfect, or so we thought. My daughter repeatedly questioned the baby's doctor about why Jennifer's eyes were not tracking together. This appearance was barely noticeable and the doctor assured her that 'the baby was only trying to look at the bridge of her nose and would grow out of it.

A group of researchers from Harvard have found evidence that telomere attrition in aging telomerase-deficient mice, heterozygous for the p53 tumour suppressor gene, promotes the development of epithelial cancers.

Aged humans sustain a high rate of epithelial cancers such as carcinomas of the breast and colon, whereas mice carrying common tumour suppressor gene mutations typically develop soft tissue sarcomas and lymphomas. This difference has been attributed to the variance between species with respect to their telomere length and regulation. Unlike the situation in humans, mice have promiscuous telomerase activity and long telomeres which has been suggested as the reason why they don't develop epithelial carcinomas.

In this study, telomerase-deficient, p53-heterozygous mice were inbred for 5 to 7 generations with the resulting mice having shortened telomeres. As they aged, half of these mice developed lymphomas and sarcomas, but unexpectedly, the remaining mice developed epithelial carcinomas. These data indicate that the telomeres from these mice may have become critically short in epithelial tissues, with the malfunctioning telomeres catalyzing genomic rearrangements that initiated and sustained the development of cancer.

Cancers develop in several distinct steps, with cells of increasing aggressiveness and capability emerging over time. Cells that lack telomerase may undergo widespread genomic disarray leading them to become cancer cells. This disarray can reach a point in which the cell is no longer viable and it dies. Alternatively, the activation of telomerase can allow the addition of telomere repeats to these mutant chromosomes, which enables their survival, and the progression of the cancer.

A great deal of research has been targeted at developing pharmacological inhibitors of telomerase, with the aim of knocking out the telomerase that enables the cancer cells to survive and replicate. However, these data suggest that removing telomerase function from these cells may lead to their death in some instances, but in cells that are still not near the 'threshold for viability', the removal of telomerase may actually cause them to mutate into more aggressive forms. This suggests that telomerase inhibitors should be used in conjunction with other forms of chemotherapy to ensure the death of all cancer cells.

Anna Liachenko, BSc, MSc
Managing Editor, Geriatrics & Aging

Despite the fact that colon cancer is preventable, over 16,000 elderly Canadians were diagnosed with the disease in 1999. One out of every three patients diagnosed with the disease, died. Prevention of colon cancer requires discovery and removal of the precursor polyp at an early stage. However, elderly patients, who are at risk of developing colon cancer are largely underscreened. The reasons range from high invasiveness of current techniques and, thus, poor patient acceptance, to inability of the current methods to efficiently detect small polyps. Fortunately, a new non-invasive and highly efficient technique--virtual colonoscopy--has recently been introduced. This article will describe the technique and compare this technique with the traditional methods of colonoscopy and barium enema.

David J. Vining and associates, at the Bowman Gray School of Medicine first described virtual colonoscopy in 1994. It is based on analysis of two sets of axial images obtained from thin-section helical computed tomography (CT) scans of the abdomen and pelvis. The procedure starts with cleansing the patient's bowel (using a standard barium enema or colonoscopy bowel preparation) followed by colonic insufflation with room air or carbon dioxide. Then, the abdomen and pelvis are scanned with the patient holding their breath for the first 15 to 20 seconds (to cover the upper abdomen) and gently respiring for the remainder of the scan.

A dramatic announcement from scientists at a meeting of the American Society of Clinical Oncology may change the lives of patients being treated for chronic myelogenous leukemia (CML). Researchers at Oregon's Health Sciences University have designed a drug that kills cancer cells but does not harm healthy tissues, a common problem with conventional chemotherapy. "What is so dramatic about this new treatment is that it is a pill people take daily", says Dr. Brian Druker, Associate Professor of Medicine. In the tests Druker and his associates conducted, 19 out of 29 patients responded positively to the therapy, with bone-marrow cell abnormalities reduced to 15% or less.

CML is a malignant hematologic disorder that predominantly affects the middle-aged and elderly. In 95% of CML cases there is an acquired reciprocal translocation of chromosomes 9 and 22 which results in a hybrid known as the Philadelphia chromosome. This Ph chromosome contains various portions of the breakpoint cluster region (BCR) and the ableson murine leukemia virus (ABL) genes. The two sets of genes are transcribed by the same promoter and eventually translated into a fusion protein that functions as an intracellular tyrosine kinase. This tyrosine kinase is involved in promoting cellular proliferation and inhibiting apoptosis and confers a survival advantage on malignant stem cells.

The new drug, called STI-571, targets the white blood cells and inhibits the BCR-ABL tyrosine kinase pathway. So far there appear to be no adverse side effects.

Alexandra Nevin, BSc

It is predicted that 70% of all neoplasms will occur in the geriatric population by the year 2020.¹ Hematologic malignancies represent a significant and clinically devastating proportion of the cancers affecting the sixty-five-plus generation. Within the spectrum of lymphoid-derived hematologic tumors, the umbrella class referred to as non-Hodgkin's lymphoma (NHL) is particularly daunting in terms of both incidence and associated mortality in the general population. Since the 1970s, the National Cancer Institute reports that NHL is one of only five malignancies for which death rates have increased, while the American Cancer Society reports that the absolute incidence of NHL has increased over 65% in the past 30 years. The determination of age-adjusted incidence rates indicates that such trends are due primarily to increases in NHL among older persons.² From a clinical perspective, elderly NHL patients represent a unique group due to the demonstration of certain age-specific characteristics, including histology type predominance, prognosis, and response to current conventional treatment. Recent advances, such as monoclonal antibody treatment, represent a promising therapeutic avenue in future treatment of specific forms of NHL in the elderly.

The Etiology of NHL
The underlying etiology of most types of NHL is still unknown, regardless of the patient's age. However, a number of risk factors have been identified for the general population.

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Cancer and Aging: Two Sides of the RecQ-Like Helicase Coin

Multiple Myeloma: The Debilitating Disease that ‘Punches Out’ the Elderly

New Technique for the Detection of Bladder Cancer

Cancer, Cellular Senescence and Longevity--The Telomere Connection

Protein Subunit May Prevent Colon Cancer

Retinoblastoma: Geriatric Implications of a Pediatric Cancer

Mutant Mice Develop More Serious Forms of Cancer

Virtual Colonoscopy--Non-invasive Procedures Holds Many Advantages for the Patient

A Cure for Chronic Myelogenous Leukemia?

The Clinical Challenge of Non-Hodgkin’s Lymphoma in the Elderly