Cancer: when our own cells become the enemy Erin Martinez, Ph.D. Trevecca University Physician Assistant Program September 30, 2013

What is cancer? = a malignant tumor benign = cells that escape their normal surroundings, invading locally and travelling to distant locations = abnormal cell mass that develops when cells grow too much benign

Moving from normal tissue to cancer Normal cells Benign tumor Basement membrane Blood vessel Malignant tumor = CANCER Bastid J, Ciancia C, Puisieux A, Ansieau S . Role of TWIST proteins in cancer progression. Atlas Genet Cytogenet Oncol Haematol. December 2009 .

What does cancer look like? Breast cancer: normal to cancer Ductal carcinoma in situ DeNardo and Coussens Breast Cancer Research 2007 9:212

What does cancer look like? Colon cancer: normal to cancer Tumor Rose and Wu. The Internet Journal of Pathology. 12:1. 2011

What does a cancer cell look like? The Hallmarks of Cancer Cell Hanahan and Weinberg, 2000.

Hallmarks of Cancer: physiological changes 1 Keeping the foot on the gas of growth 3 2 Cells don’t die easily No brakes on growth! 5 6 Cells get more blood supply Cells escape and spread 4 Cells divide forever, and ever…

Cell growth in cancer Hallmarks 1 and 2: Keeping the foot on the gas of growth and no brakes on growth! Progress though the cell cycle more quickly than a normal cell Don’t follow normal rules for stopping the cell cycle (checkpoints) http://eishinoguchi.com/checkpoint.htm

Cancer cells resist death Hallmark 3: Cells don’t die easily Things that can usually cause programmed cell death (apoptosis) DNA and protein damage lack of nutrition/oxygen buildup of waste lack of survival signals from other cells death signals from other cells Cancer cells ignore these and survive!

Cancer cells are immortal Hallmark 4: cells divide forever, and ever… Normal cells stop growing or die when telomeres are gone Cancer cells activate telomerase or do abnormal kinds of DNA recombination to survive! http://www.med.nyu.edu/skirball-lab/sfeirlab/Research.html

Cancer cells induce angiogenesis Hallmark 5: cells get more blood supply Fast growing cells beginning to form a tumor need more nutrients and need to get rid of more waste than local blood vessels can provide Promote formation of new blood vessels (angiogenesis) with signaling molecules (example: VEGF) http://www.cancer.gov/cancertopics/understandingcancer/angiogenesis/AllPages

Cancer cells are on the move Prostate cancer metastasis imaged with PET Hallmark 6: cells escape and spread Normal cells die when they loose contact with surrounding cells or the basement membrane Cancer cells gain ability to migrate locally and sometimes flow through bloodstream and grow in a distant site (metastasis) positron emission tomography (PET) scan J Nucl Med February 2006 vol. 47 no. 2 287-297

How do normal cells become cancerous? Changes in gene expression and activity most often caused by mutations Mutations = changes in DNA that alter expression or activity of the gene Two main types of genes with mutations in cancer: Oncogene – genes that normally promote growth are mutated to be hyperactive Tumor suppressor – genes that normally inhibit growth are mutated to be inactive It takes several genetic alterations to cause cancer

How do we fight cancer? First surgery, then other therapies Target fast-growing cells - Radiation - Chemotherapy Kill all fast-growing cells - bad side effects

Other new cancer therapies Anti-angiogenesis therapy Avastin – anti-VEGF antibody for metastatic colorectal cancer, and advanced non-small cell lung cancer Targeted therapy to a oncogene in a tumor cell Gleevec - inhibitor of oncogene in chronic myelogenous leukemia Erbitux – inhibitor of oncogene in colorectal and head/neck cancer Herceptin - inhibitor of oncogene in breast cancer Gleevec –BCR-Abl inhibitor Erbitux – anti EGFR antibody Herceptin – anti HER2/neu receptor Activating immune system against cancer cells Provenge – activate man’s own immune cells against prostate cells