Lec 18: Heterotypic interactions

tissues

Cancer is a disease of ____

there are many different cells types within a tumor mass

what does histopathology reveal about the types of cells within a mass?

90%

In some cases, non-neoplastic cells (tumor stroma) may account
for ___% of cells in a tumor

99%

in Hodgkin’s Lymphoma __% of cells are lymphocytes (non-
neoplastic)

___% are Reed-Sternberg cells

Communications between multiple cell types

what is heterotypic signaling?

normal: to encourage or limit proliferation of nearby cells

cancer: promote growth

how is heterotypic signaling used in normal tissue vs cancer?

1. Growth factors (PDGF, HGF, etc.)
2. Growth-inhibitory signals (TGF-beta)
3. Trophic factors supporting cell survival (IGF-1 and -2)

what are 3 signals normally sent in heterotypic signaling?

EMT and angiogenesis

heterotypic signaling by cancer cells leads to . . .

a growth factor that inhibits cell growth

what is TGF-β?

prostatic tumors grow

(Proliferating fibroblasts send signals to epithelial cells to proliferate)

what happens when TGF-β receptors are inactivated in fibroblasts?

Tumors grew much more quickly when implanted with fibroblasts

what happened when human mammary epithelial cells (HMECs) were transformed through introduction of hTERT and ras?

fibroblasts that are derived from the stroma of cancerous tissue

what are Cancer-Associated fibroblasts (CAFs)?

they are recruited from the bone marrow into the tumor, where they differentiate into macrophages

what effect do cancer cells have on monocytes?

Monocyte chemotactic protein-1 (MCP-1)

what protein is expressed by cancer cells to recruit monocytes?

Colony stimulating factor-1 (CSF-1)

what factor is released by tumor cells leading to monocyte differentiation?

tumor cells or TAMs (Tumor-Associated Macrophages)

in human breast cancer, which cells secrete VEGF to promote angiogenesis?

the more TAMs, the more microvessels

what is the correlation of TAMs and microvessels in human cancer?

MMP-9 (matrix metalloproteinase-9)

^ enzyme that breaks down ECM, releasing angiogenic growth factors

what do macrophages secrete in colon carcinoma?

• Releasing mitogenic factors for carcinoma cells
• Reorganizing the stroma to facilitate angiogenesis and carcinoma cell invasiveness

what are two things that TAMs play a major role in?

0.2 mm

(Tumor cells more than ~0.2mm become hypoxic)

what is the distance the distance oxygen can diffuse in tissue?

genetic instructions

During embryonic development, the layout of major vessels during
angiogenesis is predetermined by ________

vascular (endothelial) cells and non-vascular (parenchymal) cells

Normal formation of individual capillaries is performed through heterotypic interactions between . . .

cancerous and non-cancerous cells

Tumors build a vascular step-by-step relying on heterotypic interactions between . . .

upregulated

In areas of tumor hypoxia, genes for VEGF are _____, stimulating
production of VEGF

reduce tumor angiogenesis

what does VEGFR inhibitor ZD6474 do?

blood leakage

gaps in tumor microvasculature results in . . .

invaded beyond basement membrane

Only after tumor has _________ can tumor cells communicate with stromal cells leading to extensive angiogenesis

activators: VEGFs or FGFs

inhibitors: statins, interferon, or collagen IV fragments

what are angiogenesis activators; what are inhibitors

genetically normal cells that have infiltrated the tumor and generate the tumor vasculature

Many anti-angiogenic therapies target the . . .

Anti-angiogenic agents can increase invasiveness of tumors
Anti-angiogenic agents can increase metastatic spread of tumors

what are undesired effects of anti-angiogenic therapy?

PDGF; IGFs

____ secreted by tumor cells to activate stromal cells, which respond by releasing ____ that sustain survival of tumor cells

healing wounded epithelial tissues

For carcinomas, the acquisition of tumor-associated stroma closely resembles the process of ______