Tumor growth and spread Section 4 Tumor growth and spread

1. Biology of tumor growth The natural history of malignant tumors can be divided into four phase: A. Transformation B. Growth of transformation cells C. Local invasion D. Distant metastases

(1) Kinetics of tumor cell growth The rate of tumor growth depends on the doubling time of tumor cells, the growth fraction of tumor cells, and the loss of tumor cells in the growing lesion. ① Doubling time of tumor cells Total cell cycle time for many tumors is equal or even longer then that of corresponding normal cells.

② Growth fraction The proportion of the proliferative pool within the tumor cell population. Even in some rapidly growing tumors, the growth fraction is merely approximate 20%. ③ The degree of imbalance between cell production and cell loss

(2) Tumor angiogenesis Factors other than cell kinetics modify the rate of tumor growth. Most important among these is blood supply. Angiogenesis is requisite not only for contimled tumor growth, but also for metastasis. Angiogenesis is necessary for biologic correlate of malignancy.

Tumor associated angiogenic factors may be produced by tumor cells or inflammatory cells (macrophages) that infiltrate tumors. e. g. vascular endothelial growth factor (VEGF) basic fibroblast growth factor (BFGF)

(3) Tumor progression and heterogeneity Many tumors become more aggressive and acquire greater malignant potential over a period of time.

② Tumor heterogeneity Despite most malignant tumors are monoclonal in origin, by the time they become clinically evident, their constituent cells are extremely heterogeneous resulting from multiple mutations that accumulate independently in different cells. Thus the generating subclones are with different characteristics. A growing tumor there for tends to be enriched for those subclones that are adept for survival, growth, invasion, and metastases.

2. Tumor growth (1) Rate of growth Benign: slowly years to decades Malignant: rapidly moths to years

(2) Pattern of growth ① Expansile a. Well-demarcated and encapsulated b. Gradually c. Surgically enucleated easely. d. The particular growth pattern of benign tumors

Expansile Growth pattern(offered by Song W.Wong)

② Invasive a. Progressive infiltration, invasion, and destruction of the surrounding tissue b. Ill-defined and non-encapsuled c. The particular growth pattern of malignant tumors d. Be surgically enucleated difficultly

Invasive growth pattern

e. The steps and mechanism of invasion i. Cancerous cells attaching basement membrane Cancerous cells have more receptors of lamina and fibronectin ii. Local proteolysis iii. Locomotion

③ Exospheric a. Tumors growth projecting on the surface, booty cavities, or the lumen b. Commonly polyp, mushroom, and finger-like c. Growth pattern of both benign and malignant tumors

Exospheric growth pattern

3. Tumor spread The spread is a cheracteristic of malignant tumors (1) Local invasion Malignant tumor cells invade, penetrate local tissue fissure progressively.

(2) Metastasis Definition: metastasis connotes the development of secondary implants discontinuous with the primary tumor, possibly in remote tissue.

① Lymphatic metastasis a. This is the most common pathway for initial dissemination of carcinoma. b. Tumor cells gain access to an afferent lymphatic channel and carried to the regional lymph nodes. In lymph nodes, initially tumor cell are confined to the subcapsular sinus; with the time, the architecture of the nodes may be entirely destroyed and replaced by tumor.

c. Through the efferent lymphatic channels tumor may still be carried to distanced lymph rode, and enter the bloodstream by the way of the thoracic duct finally. d. Destruction of the capsule or infiltration to neighboring lymph nodes eventually causes these nodes to become firm, enlarged and matted together.

Lymphatic metastasis Quoted from Prof.Li Yu-Lin 《Pathology》

Lymphatic metastasis

② Hematogenous metastasis a. This pathway is typical of sarcoma but is also used by carcinoma b. Process: tumor cells →small blood vessels→ tumor emboli→ distant parts→ adheres to the endothelium of the vessel→ invasive the wall of the vessel→ proliferate in the adjacent tissue→ establish a new metastatic tumor.

c. follow the direction of blood flow c. follow the direction of blood flow. Tumors entering the superior or inferior vena cava will be carried to the lungs tumors entering the portal system will metastasize to the liver. d. Some cancers have preferential sites for metastases lung cancer offal metastasize to the brain, bones, and adrenal glands. Prostate cancer frequently metastasize to the bones. e. Morphologic features of metastasis tumors multiple, circle, scatter

Blood metastasis

③ Implantation metastasis a. Tumor cells seed the surface of body cavities b. Most often involved is the peritoneal cavity c. But also may affect pleural, pericardial, subarachnoid, and joint space.

Mechanisms of invasion and metastasis ① Invasion of the extracellular metastasis a. Loosening up of tumor cells from each other: E-adhering expression is reduced b. Attachment to matrix components: cancer cells have many more receptors of lamina and fibronectin. c. Degradation of extra cellular matrix: Tumor cells can secrete proteolytic enzymes or induce host cells to elaborate proteases.

② Vascular dissemination and homing of tumor cells a. Tumor cells may also express adhesion molecules whose ligands are expressed preferentially on the endothelial cells of target organ. b. Some target organs may liberate chmoattractonts that tend to recruit tumor cells to the site. e. g. insulin-like growth factor Ⅰ, Ⅱ. c. In some cases, the target tissue may be not an permissive environment. i. g. inhibitors of proteases could prevent the establishment of mend of a tumor cottony.

③ Molecular genetics of metastases At present, no single “metastasis gene” has been found, just son conciliates a. High expression of nm23 gene often accompanied with low metastatic potential. b. KAI-I gene, located on 11pn-2, expressed in normal prostate but not in metastasis prostate cancer. c. KISS gene, also located on human chromosome Ⅱ, analogous manner in human malignant melanoma.

(Quoted from Robbins《 Pathology Basis of disease》)

(2) Reclusive metastasis 4. Tumor recurrence Cause: (1) Tumor cell remnant (2) Reclusive metastasis

5. Grading and staging of tumor (1) The grading of a cancer attempts to establish some estimate of its aggressiveness or level of malignancy based on the differentiation of tumor cells and number of mitoses within the tumor. Grade Ⅰ: well differentiation, low malignancy Grade Ⅱ: middle differentiation, middle malignancy Grade Ⅲ: poor differentiation, nigh malignancy

(2) The staging of cancers is based on the size of the primary lesion, its extent of spread to regional lymph Medes, and metastases. Widely used is a so-called TNM system. T: primary tumor N: regional lymph node involvement M: metastases

A specific tumor would be characterized as T1, T2, T3, or T4, with increasing size of primary lesion; No, N1, N2, N3 to indicate progressively advancing nodal disease; Mo or M, according to whether there are distant metastases.