27 Malignant Neoplasms – Cellular and Systemic Effects

The Problems and Complications with Malignant Tumors:  Cellular and Systemic Levels

As a malignant neoplasm develops several problems can arise if the cancer is not treated and the malignancy persists.

Firstly, as the mass grows, it can compress blood vessels, which can lead to hypoxia of the affected tissue.  Without sufficient exchange of gases, nutrients and wastes, tissue cells become less functional and may even undergo apoptosis or unplanned cell death due to the ischemia that has occurred.  This potentially creates an area of necrosis and inflammation around the tumor.

Secondly, the tumor cells themselves can actively harm healthy neighbouring cells by secreting enzymes (e.g., proteinases), hormones, antibodies, cytokines, or growth factors in addition to potentially causing the immune system to secrete autoantibodies.

1. Enzymes:  Cancerous cells are able to facilitate their spread through the extracellular matrix (ECM) by secreting ECM proteinases which break down the extracellular matrix proteins (within connective tissue) allowing for metastasis to occur.  Furthermore, ECM destruction disrupts the structure and stability of surrounding healthy tissue and can lead to cell death.  Tumor cells have also been found to produce their own ECM proteins, remodeling their environment to support their own growth.  For example, the newly remodeled ECM promotes the inward growth of blood vessels (angiogenesis) which is partially driven by the hypoxia occurring within the growing cluster of cancerous cells.  Additionally, the newly remodelled ECM contains dense collagen and fibronectin serves as a barrier which prevents T cells from infiltrating and destroying the cancerous cells.

2. Hormones:  Abnormal hormone production by cancerous cells is rare, but can disrupt the body’s homeostasis as well as induce detrimental changes.  The effects of abnormal hormone levels may be discovered before the presence of cancerous cells.  Additionally, because many hormones can travel the bloodstream, the effects of hormones can be exerted on regions that are distant from the cancerous mass.  Examples:

• An abnormal increase in adrenocorticotropic hormone (ACTH) can lead to Cushing syndrome depicted by high cortisol levels, hypokalemia, facial hair, peripheral edema, weight gain, muscle weakness, and hypertension.
• Cancerous cells that produce antidiuretic hormone (ADH) can induce hyponatremia, increased urine osmolality, nausea, lethargy, anorexia, possibly confusion, seizures and coma.  This condition is referred to as Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH).
• Cancerous cells that produce parathyroid hormone can produce hypercalcemia.

3.  Autoantibodies: It seems that several types of antibodies may be produced in the presence of cancer.  Some cancerous cells (e.g., colorectal cancer, epithelial cancer, and prostate cancer) may produce autoantibodies.  The immune system (e.g., B cells) also can start producing autoantibodies.  Interestingly some auto-antibodies to cancerous cells have been found to inhibit tumor growth and some have been found to stimulate tumor growth.

4.  Cytokines are important cell signalling molecules and tumors have found to disrupt the production and function of cytokines.  Overall, the disruption of cytokines found in the tumor microenvironment TME have found to be with mixed effects, with many cytokines present that promote the survival, growth, and spreading of the tumor, which includes immunosuppression and inflammation.  However, some cytokines in the TME have been found to inhibit tumor growth and promote WBC activity.

5. Growth factors:  Unfortunately, many growth factors have been linked to the growth and development of metastases at all stages including: proliferation, invasion, migration, and angiogenesis. For example:

• VEGF (Vascular Endothelial Growth Factor) which promotes angiogenesis which enhances delivery of oxygen and nutrients to the tumor and promotes tumor growth.

*Excellent Therapeutic Idea:  Some new drugs mimic human antiangiogenic factors to block this & starve cancer! – good idea!  However, so far not as effective as hoped, as without blood vessels, chemotherapy drugs can’t get to the cancer

Paraneoplastic Syndrome: is defined as the clinical manifestations (signs and symptoms) that occur not directly due to the cancer, but due to the hormones, autoantibodies, cytokines and growth factors that they produce.