LMP420H1 – Cancer Pathogenesis

As a basic starting point, we will establish the outlines of the various forms of cancer, their geographical distribution and the temporal changes in cancer incidence.

Some discussion concerning the study of cancer and the myriad intersecting disciplines that inform these investigations will also form part of this session.

In this session, we will consider using the "Hallmarks of Cancer" approach first proposed by Robert Weinberg over three decades ago.

This approach discusses the essential molecular, cellular, and physiological aspects of neoplasms. This approach will be used throughout the course, thus forming one of the core aspects of our deliberations.

Using a number of large-scale, data-rich approaches, we will also begin to appreciate the outlines of the myriad molecular, genetic and cellular pathways that are involved in transformation, growth and metastasis of cancer cells.

As will become evident, while often studied as individual molecules in relatively linear pathways, the pathobiology of cancer
involves complex networks - both within cancer cells themselves and in the supporting stroma.

Part one: viruses

While the study of viruses may appear somewhat outside the "Hallmarks of Cancer" framework, their study is relevant to cancer biology on a number of levels.

Historically, they represented one of the first examples of an environmental factor giving rise to neoplasms in animals. More detailed genetic and molecular analyses showed that specific genetic elements were responsible for causing cellular transformation and were essential in the demonstration that normal genetic elements in animals were, in fact, the basis of the oncogenes that caused cellular transformation.

Other varieties of viruses also help define classes of tumour suppressor genes and lead to the discovery that a number of genes important in animal development contribute to cellular transformation.

Part two: Cancer Stem Cells

In the second part of this class, we introduce the Cancer Stem Cell model.

A number of characteristics of stem cells make this a compelling model to understand a variety of phenomena related to the phenotype of cancer cells, the refractory nature of some cancers to therapeutic interventions and the reoccurrence of cancer cells, often with long latency, following apparent remission.

While the subject is introduced here, this model will be important in discussions throughout the course amongst the other themes we cover.

Sustaining cell proliferation stands out as one of the obvious features amongst the Hallmarks of Cancer.

Here, we will take a (limited) survey of some mechanisms that normally control the cell division cycle. How the control of these mechanisms fail or are subverted to contribute to the transformed phenotype will be the essential aspect of this section.

Historical cell biology experiments suggested that the transformed phenotype was a "recessive state", suggesting that there exists suppressors of the transformed phenotype.

Now termed growth suppressors these factors are an intensely-studied area and their inactivation by, for example, tumour viruses or by mutational or silencing mechanisms have revealed the importance of "negative" regulators of the cell division cycle and their contributions to cell transformation.

Transformed cells need to be able to evade immune surveillance. Recent evidence has shown that these cells can can provide a "Don't Eat Me" signal that prevents the innate immune system from using macrophage-mediated phagocytosis to eliminate these cancer cells.

Furthermore, cancer-cell signalling can promote an inflammatory microenvironment that promotes cell growth and/or metastasis. These mechanisms also provide points of intervention where alterations of these signals could be used to block growth or, indeed, lead to immune system-dependent elimination.

In normal human diploid cells, the length of the repetitive guanine rich DNA sequence at the caps of chromosomes, telomeres, shortens with each successive replication cycle.

In the 960s, Leonard Hayflick and his colleagues discovered that once telomeres reach a critical length, they enter a permanent cell cycle arrest. This critical threshold has been termed the “Hayflick Limit.”

Many cancer types have adapted to overcome this limit by lengthening telomeres via telomerase-dependent methods as well as ALT (alternative lengthening of telomeres) mechanisms. 

A hallmark distinguishing feature of cancer cells relative to all other cells in the body is the ability to invade into nearby tissues and migrate to other areas of the body where they can infiltrate and colonize.

The ability for cancer cells to separate from its current environment, transform or dedifferentiate into a stem cell-like state in order to survive in a new microenvironment is often accomplished through loss of E-cadherin (CDH1) and associated with a process called epithelial-mesenchymal transition (EMT), respectively.

The ability for tumour cells to actively promote the growth of new blood vessels is one of the hallmarks of cancer.

The processes and reciprocal signalling cascades that are involved will be the focus of this session as will the utility of therapeutically-blocking angiogenesis as a strategy for controlling cancer growth. 

Preservation of the integrity of a cell's collection of genetic information (ie. genome) is managed by numerous processes such as DNA damage repair pathways, epigenetic mechanisms, maintenance of telomere lengths, and the management of repetitive DNA sequences.

Disruption of any of these processes may lead to an accumulation of mutations that lead to carcinogenesis. This concept of genomic instability and associated mutations are the concepts that this unit will explore.

Cell growth and proliferation requires the import and metabolism of key nutrients e.g. glucose and amino acids such as glutamine) into energy under favourable aerobic conditions and while under metabolic stress (eg. hypoxic environment or low nutrient supply).

Cancer cells demonstrate an upregulation of imported nutrients and alter the rate of metabolism, despite unfavourable conditions. 

Precision Medicine is an emerging approach applied to many diseases.

For cancer, it is most commonly associated using the genomic information within a patient’s tumour to aid in diagnosis, more accurately predict response to treatments, tailor targeted therapies, and possibly serve as eligibility to clinical research trials.