Metastasis

Mechanisms of Invasion and Metastasis

A-D, Schematic illustration of the sequence of events in the invasion of epithelial basement membranes by tumor cells. Tumor cells detach from each other because of reduced adhesiveness, and cells then attach to the basement membrane via the laminin receptors and secrete proteolytic enzymes, including type IV collagenase and plasminogen activator. Degradation of the basement membrane and tumor cell migration follow.

Stromal microenvironment and carcinogenesis

Stromal microenvironment andcarcinogenesis

Carcinoma associated fibroblasts

(prostate cancer )

The metastatic cascade. Schematic illustration of the sequential steps involved in the hematogenous spread of a tumor

Mechanisms of metastasis development within a primary tumor. A nonmetastatic primary tumor is shown (light blue) on the left side of all diagrams. Four models are presented: A, Metastasis is caused by rare variant clones that develop in the primary tumor; B, Metastasis is caused by the gene expression pattern of most cells of the primary tumor, referred to as a metastatic signature; C, A combination of A and B, in which metastatic variants appear in a tumor with a metastatic gene signature; D, Metastasis development is greatly influenced by the tumor stroma, which may regulate angiogenesis, local invasiveness and resistance to immune elimination, allowing cells of the primary tumor, as in C, to become metastatic.

Alteration

TIMPsTIMPs

TIMPsTIMPs

Matrix metalloproteinase regulation. Four mechanisms are shown: (1) regulation of synthesis by growth factors or cytokines, (2) inhibition of synthesis by corticosteroids or TGF-β, (3) regulation of the activation of the secreted but inactive precursors, and (4) blockage of the enzymes by specific tissue inhibitors of metalloproteinase (TIMPs).

(Modified from Matrisian LM: Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet 6:122, 1990, with permission from Elsevier Science.)

Cancer Stem Cells Cancer Stem Cells

(Tumor Initiating Cells T-IC's)(Tumor Initiating Cells T-IC's)

Predisposition to Cancer

Geographic And

Racial Factors

Geographic And

Racial Factors

Environmental

and

Cultural

Influences

Environmental

and

Cultural

Influences

Chronic Inflammation and CancerChronic Inflammation and Cancer

• Production of cytokines and reactive oxygen species (ROS)

• Increase in pool of tissue

stem cells

The Fire Within

Biology of tumor growth. The left panel depicts minimal estimates of tumor cell doublings that precede the formation of a clinically detectable tumor mass. It is evident that by the time a solid tumor is detected, it has already completed a major portion of its life cycle as measured by cell doublings. The right panel illustrates clonal evolution of tumors and generation of tumor cell heterogeneity. New subclones arise from the descendants of the original transformed cell, and with progressive growth the tumor mass becomes enriched for those variants that are more adept at evading host defenses and are likely to be more aggressive.

(Adapted from Tannock IF: Biology of tumor growth. Hosp Pract 18:81, 1983.)

Biology of tumor growthBiology of tumor growth