Neoplasia: Invasion and Metastasis Flashcards
Metastasis
the transfer of malignant cells from the primary site to a non-connected (secondary) site. So metastases are tumors discontinuous with the primary tumor.
Discuss the mechanisms of metastasis, including lymphatogenous, hematogenous, and cavitary.
Dissemination of cancers may occur through one of three pathways:
1. direct seeding of body cavities or surfaces (ex: ovarian ca)
2. lymphatic spread
3. hematogenous spread
(Most malignant tumors are obviously invasive. They recognize no normal anatomic boundaries! Surgical resection often difficult or impossible: even if tumor appears well circumscribed it is necessary to remove a large margin of apparently normal tissue adjacent to the infiltrative neoplasm.)
Discuss theories regarding why and how metastasis occur, including what “motivates” cancer cells in a primary tumor to metastasize
In the primary tumor it becomes advantageous to move beyond basement membrane when conditions get crowded & harsh (hypoxia caused by limited blood supply and lack of nutrients).
Then there is selective pressure to “move out” or metastasize (get away from the primary tumor site).
**An increasing body of research suggests that additional hallmarks of cancer are involved in the pathogenesis of some and perhaps all cancers. One involves the capability to modify cellular metabolism in order to most effectively support neoplastic proliferation. The second allows cancer cells to evade immunological destruction. Genomic instability endow cancer cells with genetic alterations that drive tumor progression. Inflammation by innate immune cells designed to fight infections and heal wounds can instead result in their inadvertent support of multiple hallmark capabilities, thereby manifesting the now widely appreciated tumor-promoting consequences of inflammatory responses.
explain the bias of metastasis of certain types of cancer towards certain organs.
- there seems to be something inherent in particular cells that let them metastasize to particular places and not others.
- – Breast cancers often go to ovaries and bone.
- – Kidney cancers go to thyroid.
- – GI cancers go to ovaries.
- – Thyroid cancers go to bone.
- – Prostate cancers go to bone.
Discuss four major theories to explain the bias of metastasis of certain types of cancer towards certain organs
(1) Cancer cells go to all organs equally, but only multiply in organs that have the right growth factors.
(2) Vascular endothelial cells in target organs express certain adhesion molecules (selectins) that select for particular types of cells.
(3) Organ-specific chemoattractant molecules are given off by certain organ cells that attract certain other kinds of cancer cells.
(4) Evidently, (4) is that (1) and (3) seem to be the leading contenders.
Describe the steps in the metastatic cascade, including invasion, intravasation, extravasation, and colonization and discuss what is known about how these steps occur. Steps (12):
(1) Clonal expansion, growth, diversification, angiogenesis
(2) metastatic subclone
(3) adhesion to and invasion of basement membrane (Invasion through basement membrane & ECM)
(4) passage through ECM
(5) Intravasation (getting into a blood or lymph vessel)
(6) interaction with host lymphoid cells
(7) tumor cell embolus
(8) adhesion to basement membrane
(9) extravasion (getting out of vessel at new site)
(10) metastatic deposit
(11) angiogenesis
(12) growth (ability to grow in new site)
Invasion: Invasion of the ECM is an active process that can be resolved into several steps
- Changes “loosening up” of tumor cell-cell interactions: loss of E-cadherin, for example (alterations in adhesion molecules)
- Degradation of ECM (Tumor cells can secrete proteolytic enzymes themselves or induce stromal cells to make them.)
- Attachment to ECM components (Changes in attachment of tumor cells to ECM proteins. Normal epithelial cells have receptors, such as integrins, for basement membrane laminin and collagens that are polarized at their basal surface; these receptors help to maintain the cells in a resting, differentiated state.)
- Migration of tumor cells (Locomotion is the 4th and final phase of invasion, propelling tumor cells through the degraded basement membranes and zones of matrix proteolysis.)
Process is repeated in reverse when tumor cells extravasate at a distant site***
Intravasion:
Getting into the vasulature
- Once in the circulation, tumor cells are vulnerable to destruction by: mechanical shear stress, apoptosis stimulated by loss of adhesion (anoikis) innate and adaptive immune defenses.
- Within the circulation, tumor cells tend to aggregate in clumps. Tumor cells may also bind and activate coagulation factors, resulting in the formation of emboli.
Extravasion:
Arrest and extravasation of tumor emboli at distant sites involves adhesion to the endothelium, followed by egress through the basement membrane (involving adhesion molecules (integrins, laminin receptors) & proteolytic enzymes). Of particular interest is the CD44 adhesion molecule, expressed on normal T lymphocytes and used by cancer cells to migrate to selective sites in the lymphoid tissue and overexpression of CD44 may favor metastatic spread.
-Site at which circulating tumor cells leave the capillaries is sometimes due to the anatomic location of the primary tumor (many metastases occur in the 1st capillary bed available to the tumor).
Colonization:
- “Seed and Soil” Theory Mechanisms:
1) First step in extravasation is adhesion to the endothelium: tumor cells can have adhesion molecules whose ligands are expressed by endothelial cells of the target organ. Endothelial cells of the vascular beds of various tissues differ in the expression of such ligands.
2) Chemokines: Breast cancer cells express chemokine receptors and the tissues that the cancer cells commonly metastasize to express the chemokine. Some target organs may liberate chemoattractants that recruit tumor cells to the site.
3) Some tissues are nonpermissive environment—”unfavorable soil” for the growth of tumor seedlings. Example, though well vascularized, skeletal muscles are rarely the site of metastases - Dormancy = prolonged survival of micrometastases without progression, is well described in melanoma and in breast and prostate cancer.
Discuss the role of metastasis in death by cancer: what are the ultimate effects of metastasis - what are some of the ultimate causes of mortality due to cancer?
Ultimate effects of metastasis:
- Direct: Invasive masses which interfere with normal function (the more local metastasis in an organ, the less function you get out of that organ)
- Indirect: “Paraneoplastic Syndrome” (paracrine/endocrine effects): occur in 7% to 15% of patients with cancer.
- –consequence of the presence of cancer, but not due to the local presence of the cancer cells. Thought to be due to hormones or cytokines excreted by tumor cells and/or immune response triggered by the tumor (ex. Ectopic Hormone Production, Cutaneous lesions, Arthropathies, Myopathies, Neuropathies, Multiple Thromboses, Nephrosis, cachexia, DIC)
Ultimate causes of mortality due to cancer (non-leukemic) Infection (41.6%) Organ Failure (19.2%) Hemorrhage (8.8%) Thromboembolism (12.2%) Emaciation (7.7%)