see also:

• neoplasia / cancer / tumours

• A dominant clone forms in tumours (selected by microevolutionary process) & this is the sole clone is present in the tumour & in metastases but there may be phenotypic heterogeneity with different receptors, etc. expressed.
• For a tumour to spread it must have clones with a metastatic phenotype (“seed”) that allows metastasis, a suitable tissue (“soil”) to metastasize in & a mechanism of getting there without destruction by the immune system;
• Metastases may occur early in tumor development, & the constant shedding of cells is irrelevant to metastasis.
• There is nothing that a metastatic cell can do that is not a routine task for normal cells such as lymphocytes, monocytes & neutrophils except normal cells don't appear to migrate & invade by the same mechanisms as tumour metastases;

• direct infiltration of surrounding tissues - all malignant tumours;
• tend to follow natural clefts or tissue planes & move in line least resistance;
• may be held up for some time by dense fascial sheaths;
• cartilage is resistant to tumour invasion → i/vert disc & epiph. v.late;
• may infiltrate into:
  • striated muscle cell fibres;
  • epidermis (eg. Paget's of nipple, malig. melanoma)
  • BCC spread entirely local;

• carcinomas » sarcomas have tendency to invade lymphatics
• ⇒ cord-like “permeation” within lymphatics
• ⇒ block channel
• ⇒ retrograde diversion of lymph & Ca cells
• ⇒ outlying malig. nodules (eg. skin over breast Ca);
• ⇒ local oedema (peau-d'orange in breast Ca);
• eg. lymphangitis carcinomatosa - in lung usually due to 2° (breast);

• esp. pancreas Ca & adenoid cystic Ca parotid, many other Ca → pain;

• esp. lung Ca as many vessels available, but may be missed as often covered with thrombus;
• also clear-cell Ca kidney → renal V (→ L. varicocoele);

• generally, thick elastic wall prevents invasion but:
  • lung → pulm A (may → tumour necrosis, lung infarct);

• probably invaded in every case of malignant dis., esp sarcoma;

• once mesothelium eroded, the space may be traversed by tumour cells:
  • some periph. lung Ca → directly to chest wall;

• emboli of permeated tumour cells (mainly Ca rarely sarcoma) → LN's
  • ⇒ may pass into blood via thoracic duct, etc;
• retrograde embolism to other LN's may occur if lymph blocked:
  • eg. gastric Ca blocking thor.duct @ entry into L.subclavian V
    • ⇒ spread to L. cervical nodes (Virchow's node);
• early LN involement in: breast, lung, tongue Ca;
• late LN involvement in: skin, lip Ca;

• NB. also after lymph spread into subclavian Vv (Ca » sarcoma);
• emboli after venous/small vessel invasion (sarcoma » Ca) then impact on (most die) & then penetrate a distant capillary network to proliferate, acquire own blood supply & develop into secondary tumours, mainly at following sites in order frequency:
  • liver esp. if tumour invades portal V - GIT, breast, lungs, gen/urin; sarcoma;
  • lung - breast, kidney, thyroid, sarcomata;
  • bones (red marrow) - lung (esp. oat-cell ), breast, prostate, kidney (clear-cell),
  • thyroid (foll.cell mainly); neuroblastoma;
  • osteoplastic lesions - prostate (occas. breast, colon, neuroblastoma);
  • brain - lung, breast, melanoma;
  • adrenal (med>cort) - lung (esp. oat-cell), breast,
  • skin (face, scalp) - lung, breast, melanoma;
• NB. sarcomata metastasise early, mainly → lung » liver/brain » bone;
• NB. malignant brain tumours rarely → outside cranial cavity (no lymph);
• NB. these metastases may lie dormant for a long time & although may have occurred prior to lymph node involvement, the LN's may become evident 1st !!

• when tumour invades a serosal layer of a viscus → inflamm. response → effusion, & may allow malig. cells to detach & be swept away in effusion & set up seedlings elsewhere on serosal wall:
• peritoneal: stomach, colon, ovary → greater omentum, Pouch of Douglas; ovaries;
  • NB. Krukenberg bilat. ov. tumour - ? from perit. or lymphatics;
  • usually 1° mucoid tumour - stomach»colon/breast;
• pleural: lung, breast , lung 2°'s → pericardium;
  • NB. Meig's synd.: benign ov. fibroma → ascites + pleural effusion!!
• CSF: 1° cerebral tumours → subarachnoid space → spinal theca;
  • esp. medulloblastoma, oligodendroglioma, ependymoma;
• Spread along epithelial-lined spaces:
  • papillary tumours renal pelvis → scattered tumours along ureter & bladder;
  • surgical implantation of tumour cells at incisions or along needle tracks;

• over-activity of a shape-less protein MYC promotes cancer growth and is a critical transcription factor whose aberrant activity is implicated in the growth and spread in more than 75% of human cancers ¹⁾

• Growth: overcome allogeneic inhibition by nearby tissue cells, etc.;
• Angiogenesis if > 2mm (similar to wound healing):
  • degree of angiogenesis often predictive of metastatic disease;
  • degradation of basement membrane, extracellular matrix;
  • endothelial migration & proliferation, then organisation & maturation;
  • needs:
    • proteolysis (see under tissue invasion)
    • stimulation of new capillaries, etc
  • regulated by balance between:
    • fibroblast growth factors;
    • transforming growth factors;
    • inhib. by high dose steroid & heparin;
    • inhib. factors;
• Tissue invasion:
  • tissue matrix proteolysis
  • balance b/n:
    • matrix metalloproteinases (released as zymogens, best @ pH7)
    • interstitial collagenases (collagen I/II/III);
    • gelatinases (gelatin & collagen IV)
    • stromelysins (collagen IV & proteoglycans)
    • tissue inhib. of metalloproteinases (TIMPs)
  • cell detachment from main mass (ie. homophilic cell/cell interactions decr.);
  • down regulation of cadherin expression esp. if loss of differentiation;
    • ⇒ increased migratory & invasiveness;
  • increased cell-matrix interactions
    • correlates with tumour progression in some tumours;
    • assists in providing traction at migrating front of tumour cell & is released from hind part to allow movement;
    • up-regulation of fibronectin & vitronecton receptors (integrins) that bind to Arg-Gly-Asp (RGD) tripeptide sequences in extracellular matrices;
  • cell motility increased
    • due to cell receptor binding motility stimulating factors (motogenic cytokines):
      • scatter factor produced by fibroblasts
        • same as hepatocyte growth factor (HGF);
        • receptor is a transmemb. tyr. kin. encoded by c-MET oncogene!
        • autocrine motility factor (AMF) from cell itself → acts via G protein;
        • migration stimulating factor (MSF)

• Survival - Host interactions ( with cytotoxic T cells, etc):
  • down regulation of expression of MHC class I molecules, or,
  • lack of surface neoantigens (tumour-specific antigens)
    • tumour-spec. transplantation Ags (TSTAs)
      • rejection via cytotox. T cells &/or Ig/compl-mediated cytotoxicity;
      • occas. protection “immunol. enhancement” as Ig hide Ag from T cells;
    • oncofetal antigens (tumour markers in blood but not involved in rejection)
      • carcinoembryonic Ag (CEA) - some colon Ca in tumour mass;
      • alpha-fetoprotein - liver Ca, germ-cell tumours; stomach/pancreas;
    • other antigens, often tumour specific
      • T antigen - nucleus od DNA-virus induced tumours;
      • Ca antigen - many malignant tumours;
  • lack of expression of ICAM-1 (needed for stable binding to T cell LFA-1 integrin)
  • release of soluble forms of ICAM-1 that would bind T cells & thus decr. T cell availability to bind ICAM-I on the tumour cell;
  • NB. circulating Ig seems to have little restraint on tumours but NK cells may do.
  • spontaneous regression may occur due to immune response to some tumours:
    • Burkitt's, chorioCa, melanoma (before metastasis); clear-cell kidney (rarely);
  • immunosuppressed & immunocompromised are @ incr. risk of neoplasia;
  • immune-complexes formed may → nephrotic synd., arthralgia, skin eruptions;

• adherence to endothelial cell via:
  • VLA-4/V-CAM - melanoma
  • CD44/??
  • sialylLex antigen/ELAM-1 - colorectal Ca
  • CD44-hyaluronate-CD44
• emigration out of blood vessel via:
  • retraction of endothelial cell exposes basement membrane receptors;

• May be that parental populations of tumour cells contain clones of varying metastatic capacity depending on the presence/abscence of the above qualities;
• Possible metastogenes are:
  • nm23:
    • appears to be a metastasis suppressor gene with loss of expression correlating with poor survival in breast cancer & converse true;
    • considerable homology with abn. wing disc gene of fruit fly!!
    • ? codes for a nucleoside diphosphate (NDP) kinase which may be involved in microtubule assembly/disassembly & signal transduction through G proteins
      • ie. cell adhesion & motility!
  • genes which control expression of phosphatases of regenerating liver (PRLs)
• a newly discovered mechanism for metastatic behaviour relates to cancer cells hijacking the protein GRP78
  • GRP78 normally acts as a chaperone protein, assisting in the folding or unfolding of larger proteins, which then affects whether they're biologically active and functional.
  • GRP78 is usually found in the endoplasmic reticulum part of a cell, however, under stress or in cancer cells, it moves to the nucleus where it can control gene expression including the gene EGFR which is linked to cancer as well as other genes involved in cell migration and invasion
  • it also seems that GRP78 stops the protein ID2 from doing its regular job, which is limiting the activity of genes involved in cell migration, including EGFR

• As important causal factor:
  • unopposed oestrogen (Rx or granulosa cell tumour ovary) → uterine Ca
  • high doses oestrogen → breast Ca
  • ? OCP → hepatic adenoma & focal nodular hyperplasia liver occas. & rarely hep. Ca;
  • maternal diethylstilboestrol 1st TM → clear-cell adenoCa vagina in daughters (9 per 1000);
  • androgen Rx → hepatocellular Ca & hepatic adenoma (rarely);
• Hormone dependent tumours - important in maintaining growth:
  • prostate Ca:
    • androgens → Rx of Ca: castration, DES, GnRH analogue → decr.FSH/LH
    • ketoconazole → decr.FSH/LH; anti-androgens;
  • 30% breast Ca:
    • oestrogens, prog, PRL, GH, plac. lactogen (esp. in pre-menopausal);
      • ⇒ Rx of Ca: oophorectomy; tamoxifen; bilat. adrenalectomy;
      • glucocorticoids → decr. adrenal; high dose E??;
  • thyroid Ca (usually well-diff.):
    • TSH → Rx of Ca by thyroxine → decr. TSH;
  • metastatic endometrial Ca & renal Ca may respond to Rx with prog.
  • clear-cell Ca kidney sometimes responds to Rx with oestrogen;
• pregnancy accelerates: breast Ca, Cx Ca, melanotic & neurofibroma hamartomata;
• role of steroid receptor coactivator (SRC) SRC3
  • SRC3 is over-expressed in tumour cells and in Treg cells
  • a 2023 study showed mice with Treg SRC3 knockout are able to eliminate both breast and prostate cancer both in short term and in long term ²⁾

• cancer cells often release tumor-derived exosomes (TDEs) which are tiny vesicles containing crucial bioactive components which play key roles in cell communication and cancer progression.
• in Dec 2023, an innovative microfluidic magnetic detection system (μFMS) was developed for analyzing tumor-derived exosomes (TDEs), potential biomarkers for cancer diagnosis. It has high sensitivity and specificity, coupled with its potential for easy integration into clinical settings, pave the way for its use in early cancer diagnosis and monitoring.³⁾