Biotech Values

[DewDiligence]

The Cancer Stem Cell:
Evidence for its Origin as an
Injured Autoreactive T Cell

[This research is not directly apropos to a particular company I’m aware of, but cancer stem cells are a topic investors will doubtless be hearing more about. Please see #msg-9803820 and #msg-2482896 for related discussions.]

http://www.molecular-cancer.com/content/pdf/1476-4598-5-6.pdf

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Molecular Cancer 2006, 5:6 doi:10.1186/1476-4598-5-6

14 Feb 2006
By Peter Grandics
A-D Research Foundation 5922 Farnsworth Ct, Carlsbad, CA 92008 USA

Abstract

This review explores similarities between lymphocytes and cancer cells, and proposes a new model for the genesis of human cancer. We suggest that the development of cancer requires infection(s) during which antigenic determinants from pathogens mimicking self-antigens are co-presented to the immune system, leading to breaking T cell tolerance.

Some level of autoimmunity is normal and necessary for effective pathogen eradication. However, autoreactive T cells must be eliminated by apoptosis when the immune response is terminated. Apoptosis can be deficient in the event of a weakened immune system, the causes of which are multifactorial. Some autoreactive T cells suffer genomic damage in this process, but manage to survive. The resulting cancer stem cell still retains some functions of an inflammatory T cell, so it seeks out sites of inflammation inside the body. Due to its defective constitutive production of inflammatory cytokines and other growth factors, a stroma is built at the site of inflammation similar to the temporary stroma built during wound healing.

The cancer cells grow inside this stroma, forming a tumor that provides their vascular supply and protects them from cellular immune response. As cancer stem cells have plasticity comparable to normal stem cells, interactions with surrounding normal tissues cause them to give rise to all the various types of cancers, resembling differentiated tissue types. Metastases form at an advanced stage of the disease, with the proliferation of sites of inflammation inside the body following a similar mechanism. Immunosuppressive cancer therapies inadvertently re-invigorate pathogenic microorganisms and parasitic infections common to cancer, leading to a vicious circle of infection, autoimmunity and malignancy that ultimately dooms cancer patients. Based on this new understanding, we recommend a systemic approach to the development of cancer therapies that supports rather than antagonizes the immune system.

Introduction

Understanding the pathomechanism of cancer is of primary interest in medical research. In the past century, several mechanisms were proposed: It was hypothesized that cancer arises out from a single cell that loses its differentiated state through sequential mutations [1]. This initiation-promotion-progression concept explains the steps in a sequential process [2]. Later, this hypothesis led to the mutagenic and recently the oncogenic theories which hypothesize that defects in tumor suppressor genes are responsible for the development of cancer [3]. The impairment of cell-to-cell communication as a cause of cancer has also been postulated [4].

Mutations and other genetic abnormalities observed in cancer cells could also be caused by environmental effects, e.g., chemical carcinogens or life style factors such as alcohol or tobacco consumption or drug abuse [5]. The discovery of the cancer stem cell [6-8] lent support to the theory that cancer may develop out of a single cell, and raised the question of cancer stem cells arising from normal stem cells [9]. Indeed, if normal stem cells could undergo the type of mutations observed in tumor cells, this would potentially compromise the genetic stability of the organism. Therefore, the likelihood that normal stem cells are extremely well protected is demonstrated by their resistance to radiation and toxins [9].

One fascinating finding is that immunosuppressive cytotoxic antineoplastic therapies may on occasion cause the regression of a clinically established cancer. At first, applying this as a therapeutic strategy may seem counterintuitive, considering the fundamental role of the immune system in protecting the body against infectious organisms and aberrant cells. In addition, cancer itself is frequently immunosuppressive, so exacerbating a preexisting immunosuppression may not seem like a rational strategy. In this light, it appears paradoxical that the same degree of immunosuppression that is lethal in a bacterial or fungal infection actually benefits cancer suppression. In other words, the deletion of the T cell compartment that accompanies cytotoxic antineoplastic therapies [10] may facilitate cancer regression. This suggests that cancer itself may arise out of the immune system, potentially from the T cell compartment, which would explain why the suppression of cellular immunity could also lead to the suppression of the disease.

Another observation is that tumor cells are poorly immunogenic, despite the fact that tumor cells are antigenic [11,12]. Therefore, they do not generate a T cell-mediated immune response, and if so, it is of low intensity [13]. If tumor cells were derived from injured lymphocytes, particularly T cells that still share some functional properties with their normal counterparts, an immune tolerance to cancer cells could be explained, as the immune system is not made to attack itself. In pathological situations, T cells do attack self-tissuein a manner reminiscent of the autoreactive nature of cancer cells which have the ability to attack and invade host tissues. In other words, cancer cells behave like autoreactive lymphocytes. Here, we explore the evidence suggesting that such a mechanism could be at work during the development of cancer.

The prevalent genetic theories of cancer are built upon observations of genetic abnormalities in tumor cells. These theories do not generally take into account the demonstrated importance of environmental factors in human cancer development. In a previous paper [14] we have shown that specific dietary deficiencies mimic the effects of chemical or radiation damage to DNA, which we propose plays an important role in human carcinogenesis and tumorigenesis. This observation allows us to consider cancer as a single disease, possibly developing from a single cancer stem cell. Based on this, we could assume that the observed genomic abnormalities in cancer cells are an effect rather than the cause of the disease. This idea also points to the direction of upstream events preceding the development of the malignant cell. We propose that identifying these events will be fundamental to understanding the pathomechanism of cancer. By exploring the functional similarities between lymphocytes and cancer cells, we provide an insight into this realm of possible upstream events.
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