increased cell proliferation. Reversible
loss of uniform appearance and architectural disruptions (really bad looking cells are called anaplastic). Dysplasia is often indicative of an early neoplastic process. Reversible
“new growth” -- the point of no return – a cancer, whether benign or malignant
Stepwise mutations results in a progression of changes --> CANCER. Ex:
adenoma vs carcinoma
"oma" simply means tumor or growth. Adenoma= benign tumor growing up out of epithelial (into lumen or out onto skin for example). Carinoma= invades below the basement membrane. Epithelial and malignant. Malignancy=invasion (growing down beneath BM)
is the spread of a disease from one organ or part to another organ or part. Hallmark of malignancy
Why do we need to understand metastasis?
The metastatic lesion may be the presenting lesion and be important for DIAGNOSIS The extent of disease will determine the appropriate THERAPY - surgery, chemo tx, radiation tx The extent of metastasis determines PROGNOSIS - tumor Grade (histologic) and tumor Stage (how far it has spread)
tumor cell heterogeneity
- the metastatic cells are different from the primary tumor
-also, cells within the primary tumor are different from one another
(4) Pathways of tumor spread
(1) Local Invasion – many types of carcinomas (2) Direct seeding - ovarian ca in peritoneum (3) Lymphatic spread - most common for carcinomas, breast ca, lung ca. Also seen with sarcomas. Lymph nodes are the first line of defense. (4) Hematogenous spread - most common for sarcomas, but also seen in renal and liver ca. Mets to liver and lung.
(12) Steps of Tumor Invasion
Step 1-4: Invasion through ECM.
Step 5 - Vascular dissemination.
Step 6 - Circulation of tumor cells.
Step 7 - Attachment at a distant site.
Step 8 - Extravasation at a distant site.
Step 9 – Tumor cell attachment at a distant site.
Step 10 – Growth at a distant site.
Step 11 - Angiogenesis.
Step 12 - Evasion of the antitumor immune response.
Steps 1-4: Invasion of ECM (4 key points)
1) Epithelial cells detach from eachother without undergoing apoptosis (normally prevents wandering cells. Cell has acquired mutation in suppressor genes prior to separation).
2) Adhesion to basement membrane. Cell oriented in basal direction (opposite of normal). KEY STEP: epithelial to mesenchymal transition.
3) Proteolytic dissolution of BM by proteases (matrix metalloproteinases, collagenases, etc)
4) Locomotion of cell through ECM via chemotactic factors. Realignment of ECM fibers to radiate out from tumor (like a highway along which cell travels)
Step 5: Vascular dissemination
Intravasation: cell enters into blood vessels or lymph.
Highly vascular tumors have higher metastatic rates. Proximity of organs determines metastsis location
Step 6: Detachment from endothelial cells and circulation of tumor cells
Ciruclation as tumor emboli after separation from endothelial cells
May be covered with other non-malignant cells such as platelets
Step 7: Attachment to endothelium at distant site
Reattach to endothelium.
Certain tumor cells may recognize or attach more easily to certain tissues/organs. Uses adhesion molecules (selectins, integrins, CD44)
Step 8: Extravasation at distant site
Enters into the new organ/tissue.
Paget's seed/soil hypothesis
Setp 9: Attachment to ECM/stromal cells at distant site
The milieu at the distant site Paget’s seed/soil hypothesis.
Note: Some tumors attach but cannot invade, e.g. ovarian carcinoma in the peritoneum
Step 10: Growth at distant site
Tumor attempts to degrade ECM to make room for growth. Uses IL-6 to degrade surrounding tissue and as a growth factor to grow.
Note: Growth restricted to certain sites (eg cant grow in tough cartilage)
Step 11: Angiogenesis
Tumor needs blood vessles to grow, and make bFGF and VEGF
Tumor vasculature may be sensitive target for chemotherapy or radiation
Step 12: Evasion of antitumor immune response
Some of the tissues express death triggers, (e.g. FasL) which induces apoptosis of infiltrating cytotoxic T lymphocytes.
Also tumors can hide out in immune privileged tissues (testes, brain)
"3-pronged" clinical approach to cancer
(1) Surgery: remove primary tumor. ineffective for metastasis
(2) Radiation therapy: toxic but effective for local metastasis
(3) Chemotherapy: effective but limited by bioavailability and vascular access to metastasis. Also tumors become resistant so must give many diff types
-1 in 200 Americans will receive a cancer diagnosis in 2010. -2 in 5 Americans will receive a cancer diagnosis in their lifetime. -1 in 30 Americans are currently living with cancer. ~ 1500 people die each day from cancer in the U.S. -1 in 5 Americans will die of cancer
Hallmarks of malignancy
Invasion and Metastasis
What determines tumor grade?
What determines tumor stage?
Extent of spread
Paget's seed/soil hypothesis
Metastatic cell has to be put in the right environment in order to grow
Why is it important to use combinatorial approaches in cancer therapy?
1) tumor cell heterogeneity
2) high mutation rate
Summary of invasion/metastasis
3) Proteolytic dissolution
12) Evasion of immune response